Children's Cardiomyopathy Foundation
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RESEARCH

AWARDED GRANTS

Steven Greenway, MD

"Modeling Novel Therapeutics for DCMA,
a Mitochondrial Cardiomyopathy"
University of Calgary, Alberta, Canada
2018 Amount Awarded - $49,184

Cardiomyopathies are a diverse group of disorders with outcomes largely based on underlying cause and age of onset. For example, 14.2% of infants with hypertrophic cardiomyopathy do not survive beyond the first year after diagnosis as compared to 0.8% of older children. Furthermore, current understanding of the underlying genetic etiology of pediatric cardiomyopathy is largely based on adult studies extrapolated to children. Earlier age of onset suggests the involvement of different biological mechanisms. Despite the availability of routine clinical testing panels, the genetic cause remains unknown in the majority of children. Thus, the underlying mechanism of disease development in pediatric cardiomyopathy is largely unknown. As such, therapeutic regimens primarily focus on symptomatic management without affecting the underlying disease progression. This study will develop a human disease model of infantile hypertrophic cardiomyopathy using induced pluripotent stem cells and gene editing techniques. This will allow studying the genes and proteins involved in the development of hypertrophy and leading to impaired heart function. Induced pluripotent stem cells provide a robust method for functional studies to elucidate the damaging effects of novel genetic changes, furthering knowledge about the genetic mechanisms of pediatric cardiomyopathy. Moreover, generated heart cells serve as a human model for cardiomyopathy, which can be used as a platform to test new drugs that can then be translated into treatments specifically targeted to children.

Amy Kontorovich, MD, PhD

"Elucidating the Genetics of Myocarditis-Related Cardiomyopathy"
Icahn School of Medicine at Mount Sinai, New York, NY
2018 Amount Awarded - $50,000

Cardiomyopathies are a diverse group of disorders with outcomes largely based on underlying cause and age of onset. For example, 14.2% of infants with hypertrophic cardiomyopathy do not survive beyond the first year after diagnosis as compared to 0.8% of older children. Furthermore, current understanding of the underlying genetic etiology of pediatric cardiomyopathy is largely based on adult studies extrapolated to children. Earlier age of onset suggests the involvement of different biological mechanisms. Despite the availability of routine clinical testing panels, the genetic cause remains unknown in the majority of children. Thus, the underlying mechanism of disease development in pediatric cardiomyopathy is largely unknown. As such, therapeutic regimens primarily focus on symptomatic management without affecting the underlying disease progression. This study will develop a human disease model of infantile hypertrophic cardiomyopathy using induced pluripotent stem cells and gene editing techniques. This will allow studying the genes and proteins involved in the development of hypertrophy and leading to impaired heart function. Induced pluripotent stem cells provide a robust method for functional studies to elucidate the damaging effects of novel genetic changes, furthering knowledge about the genetic mechanisms of pediatric cardiomyopathy. Moreover, generated heart cells serve as a human model for cardiomyopathy, which can be used as a platform to test new drugs that can then be translated into treatments specifically targeted to children.

Shelley Miyamoto, MD
Carolyn Ho, MD
Kika Sucharov, PhD

"Circulating MicroRNA in Genotype-Positive Hypertrophic Cardiomyopathy"
University of Colorado, Denver, CO
2018 Amount Awarded - $50,000

Cardiomyopathies are a diverse group of disorders with outcomes largely based on underlying cause and age of onset. For example, 14.2% of infants with hypertrophic cardiomyopathy do not survive beyond the first year after diagnosis as compared to 0.8% of older children. Furthermore, current understanding of the underlying genetic etiology of pediatric cardiomyopathy is largely based on adult studies extrapolated to children. Earlier age of onset suggests the involvement of different biological mechanisms. Despite the availability of routine clinical testing panels, the genetic cause remains unknown in the majority of children. Thus, the underlying mechanism of disease development in pediatric cardiomyopathy is largely unknown. As such, therapeutic regimens primarily focus on symptomatic management without affecting the underlying disease progression. This study will develop a human disease model of infantile hypertrophic cardiomyopathy using induced pluripotent stem cells and gene editing techniques. This will allow studying the genes and proteins involved in the development of hypertrophy and leading to impaired heart function. Induced pluripotent stem cells provide a robust method for functional studies to elucidate the damaging effects of novel genetic changes, furthering knowledge about the genetic mechanisms of pediatric cardiomyopathy. Moreover, generated heart cells serve as a human model for cardiomyopathy, which can be used as a platform to test new drugs that can then be translated into treatments specifically targeted to children.

Teresa M. Lee, MD, MS
Masayuki Yazawa, PhD

“Human Induced Pluripotent Stem Cell Model of Hypertrophic Cardiomyopathy”
Columbia University, New York, NY
2017 Amount Awarded - $50,000

Cardiomyopathies are a diverse group of disorders with outcomes largely based on underlying cause and age of onset. For example, 14.2% of infants with hypertrophic cardiomyopathy do not survive beyond the first year after diagnosis as compared to 0.8% of older children. Furthermore, current understanding of the underlying genetic etiology of pediatric cardiomyopathy is largely based on adult studies extrapolated to children. Earlier age of onset suggests the involvement of different biological mechanisms. Despite the availability of routine clinical testing panels, the genetic cause remains unknown in the majority of children. Thus, the underlying mechanism of disease development in pediatric cardiomyopathy is largely unknown. As such, therapeutic regimens primarily focus on symptomatic management without affecting the underlying disease progression. This study will develop a human disease model of infantile hypertrophic cardiomyopathy using induced pluripotent stem cells and gene editing techniques. This will allow studying the genes and proteins involved in the development of hypertrophy and leading to impaired heart function. Induced pluripotent stem cells provide a robust method for functional studies to elucidate the damaging effects of novel genetic changes, furthering knowledge about the genetic mechanisms of pediatric cardiomyopathy. Moreover, generated heart cells serve as a human model for cardiomyopathy, which can be used as a platform to test new drugs that can then be translated into treatments specifically targeted to children.

Wendy Chung, MD, PhD

“Impact of Genetic Testing For Cardiomyopathies on Children and Their Families”
Columbia University, New York, NY
2017 Amount Awarded - $50,000

Cardiomyopathy is a clinically and genetically heterogeneous cardiac condition affecting individuals of all ages. Given the autosomal dominant mode of inheritance of many cardiomyopathies, the incomplete penetrance, and the variability in age of onset and severity even within a family, there are implications for other family members including children when cardiomyopathy is diagnosed within a family. Genetic testing for cardiomyopathy in patients of all ages, including children and adolescents, is becoming more common. However, the impact of genetic testing on children and their families is largely unexplored. Genetic testing during adolescence can have a significant impact on the formation of identity, particularly when predicting future risk in asymptomatic individuals. Studies in families with other autosomal dominant conditions, including familial adenomatous polyposis and hereditary breast cancer, have demonstrated significantly higher cancer-specific distress than their peers. This was strongly associated with higher maternal anxiety and poorer family communication. This study involving 8 study sites will describe the overall impact of cardiomyopathy genetic testing on psychosocial well-being, family relationships, and quality of life of patients and their parents. This will be achieved through online questionnaires and semi-structured interviews to determine if there are opportunities to improve this process for families in the future.

Juan Alejos, MD
Patricia Lester, MD

"Integrated Family-Centered Behavioral Health Screening & Preventive Intervention for Pediatric Cardiomyopathy"
University of California, Los Angeles, CA
2016 Amount Awarded – $50,000

Having a child with cardiomyopathy can impact the entire family, and distress in vulnerable families can affect patient behavioral health and medical health outcomes. Given the costs, transportation issues, time, and stigma associated with mental health care, preventive behavioral health programs that can be delivered at a distance to overcome common barriers to engagement and access to care are needed. The proposed project, Families OverComing Under Stress – Pediatric and Adolescent Cardiology (FOCUS-PAC), offers a novel approach to address this need. FOCUS-PAC involves family-centered behavioral health screening with guided feedback in the outpatient clinic setting, coupled with a trauma-informed intervention delivered via in-home video-teleconferencing (VTC). The VTC component includes: 1) ongoing trauma-informed psychoeducation and developmental guidance, 2) development of positive and effective parenting, and family-level resilience skills such as communication, emotional regulation, goal setting, and problem solving, and 4) creation of a family narrative to enhance positive meaning making, co-parenting, parent-child relationships, as well as family cohesion and support. Pediatric CM patients (ages 8-18) and families will be recruited from the outpatient cardiology clinic at UCLA Children’s Mattel Hospital. Findings from this study can provide a road map to an effective implementation of an innovative integrated family-centered screening and preventive intervention to improve behavioral health outcomes and treatment adherence outcomes for cardiomyopathy patients.

Angeliki Asimaki, PhD

"The Role of GSK3? in the Pathogenesis of Arrhythmogenic Cardiomyopathy"
Beth Israel Deaconess Medical Center, Boston, MA
2016 Amount Awarded – $50,000

Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease characterized by ventricular arrhythmias and sudden death in young individuals and athletes. Analysis of myocardial samples from patients has advanced our understanding of ACM. Cardiac samples, however, are particularly difficult to obtain in children, who may be carriers of pathogenic mutations but do not manifest the disease phenotype. From previous research, buccal mucosa cells from patients with ACM exhibit similar subcellular abnormalities to the heart and can be used as a surrogate tissue for analysis. In collaboration with Dr. Dominic Abrams, Director of the Inherited Cardiac Arrhythmia Program at Boston Children’s Hospital, buccal smears from children treated and evaluated at the clinic will be collected. This study will address the following areas for the first time: 1) at which age do subcellular abnormalities first appear and how does this correlate with clinical onset of disease? 2) can mutation status be predicted simply by immunostaining a buccal smear? 3) do gene carriers with normal buccal cells show changes in response to exercise or medication? and 4) do buccal mucosa cells show abnormalities in children with dilated cardiomyopathy, and if so how does this correlate with arrhythmias? It has been shown that living buccal cells can be collected, maintained in culture and made practical for use in children. This will provide researchers with a highly valuable tool for studying the mechanisms of disease pathogenesis. Because buccal mucosa cells can be readily obtained without risk and at minimal cost, their use as a surrogate tissue for the heart may be a game-changing tool in evaluating children with inherited cardiomyopathies.

Bahig M. Shehata, MD

"Genetic Analysis to Identify Inheritance Patterns in Histiocytoid Cardiomyopathy"
Emory University School of Medicine, Atlanta, GA
2016 Amount Awarded – $49,552

Histiocytoid cardiomyopathy (HC) is a rare form of cardiomyopathy, observed predominantly in newborn females, which is fatal unless treated early in life. Over 100 HC cases have been reported in the literature, but the prevalence is likely to be higher since many cases may have been misdiagnosed as Sudden Infant Death Syndrome (SIDS). The molecular genetic basis of HC was unknown despite several hypotheses in medical literature. After observing familial tendency, a HC registry was started in order to collect clinical data and perform analyses with the objective of identifying the causative gene(s). The registry currently houses over 150 cases and further registry details can be found at spponline.org. A casual gene was recently identified in the form of a premature stop codon in multiple cases of HC involving the NDUFB11 gene, which was published in American Journal of Medical Genetics in April 2015. This discovery was the first breakthrough in the molecular genetic basis of HC. Data from the registry indicates a 5% familial tendency; however, the true percentage is likely much higher, as several families have reported several unexplained miscarriages. The proposed study will analyze families with multiple HC cases and families with a single affected child in order to further explore the molecular and genetic basis of HC including, the familial tendency. DNA will be extracted, and targeted exome sequencing of both whole blood samples of family members and the living affected children, as well as samples from paraffin embedded tissue from the deceased affected patients will be completed. Understanding the effect of mutations in HC patients on mitochondrial function will allow for new therapeutic interventions to be developed for affected children, as well as offer opportunities to improve prevention, monitoring, and early treatment of identified carriers.

Noah Weisleder, PhD

"Targeting Membrane Repair to Treat Pediatric Dilated Cardiomyopathy"
Ohio State University, Columbus, OH
2016 Amount Awarded – $50,000

Dilated cardiomyopathy (DCM) is the most common form of pediatric cardiomyopathy, which results from the death of heart cells in a child. When these cells die, the heart loses some of its function and continues to lose more cells as the affected child ages. In many forms of DCM, and particularly in DCM associated with muscular dystrophy, the membrane that surrounds the heart cells break and cause the heart cell to die. This study will determine if a new method for increasing the ability of heart cells to repair themselves can act as a treatment for child onset DCM. The study will focus on increasing the ability of these heart cells to repair its damaged membranes and determine if this can improve the disease associated with DCM. A new therapeutic protein drug or a new gene replacement therapy will be tested to minimize the symptoms of DCM in a mouse model of this disease. These therapies may prove to be effective for many types of DCM since one common aspect of the pathology associated with different types of DCM is heart cell death. Increasing the repair capacity of heart cells could have broader therapeutic application to other DCM types that have compromised integrity of their membranes.

Richard J. Czosek, MD

"Automated ECG Screening for Hypertrophic Cardiomyopathy"
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
2015 Amount Awarded – $28,200

Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young athletes, and has an estimated prevalence of 1:500 in the population. Proper diagnosis and treatment can prevent the vast majority of sudden cardiac events in patients with HCM. Unfortunately, many HCM patients have no clinical symptoms or early warning signs that allow for early diagnosis and treatment. Screening for HCM in the general population of young adolescents has been prohibitive in the United States secondary to cost and the inability of current screening methods to identify patients with adequate sensitivity while minimizing the amount of healthy patients inadvertently screened as having HCM. This research study is aimed at developing an automated screening tool for identification of patients with HCM. Using electrocardiograms from patients with known HCM, this project will develop a computerized algorithm designed specifically to detect the changes seen in patients with HCM. This screening tool can then be refined to identify the highest percentage of patients with disease while attempting to limit misclassification of healthy patients leading to unnecessary family stress and additional cost burden to the medical system. It is expected that an automated tool to screen for hypertrophic cardiomyopathy will reduce extraneous costs and maximize the number of young individuals that can be screened. Through reductions in resource utilization, it is possible to bring down the cost of population based screening, and it may allow for universal screening of all young individuals. By allowing cost effective screening, more at risk adolescents and young adults can be identified and associated sudden death events can be prevented.

Sharlene Day, MD

"Disease Pathways for MYBPC3 Mutations in Hypertrophic Cardiomyopathy"
University of Michigan, Ann Arbor, MI
2015 Amount Awarded – $50,000

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart condition, and can cause sudden cardiac death and congestive heart failure. Current treatments help to treat symptoms but do not change the underlying disease process. While many of the genes that are affected in HCM patients have been identified, little is known about how they cause disease. Changes in the DNA, called mutations, can alter the structure of the protein that it encodes. Mutations in the most commonly affected gene in HCM, myosin-binding protein C, often lead to proteins that are shortened because they only being produced from one instead of two copies of the gene. It is uncertain whether a lower amount of the normal protein or the presence of the abnormal protein, is primarily responsible for causing HCM. From earlier studies, it was discovered that there is no significant reduction in the amount of normal myosin binding protein C in HCM patients with myosin binding protein C mutations. Therefore, this study will determine whether the mutant protein is causing many of the manifestations of HCM. The goal will be to eradicate these abnormal proteins from cells and alleviate the stress that they place on the surveillance systems that control the flow of proteins within cells. It is believed that the shortened mutant proteins are associating with helper proteins called chaperones to prevent them from being toxic to the cells. This study will try to enhance the activity of these chaperones to see if this facilitates their clearance. We expect that these studies will lay the groundwork for the future application of new therapies that target the underlying disease process, rather than treat symptoms and complications as they arise.

Mario Delmar, MD, PhD

"Visual Proteomics for Personalized Assessment of Risk in ARVC Families"
New York University School of Medicine, New York, NY
2015 Amount Awarded – $50,000

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by replacement of heart muscle with scarred and fatty tissue, and high propensity to arrhythmias. Because signs of heart damage in the early stages may not be present, ARVC is often undiagnosed in children who may succumb to sudden cardiac death. Genetic testing represents a major advance in identifying individuals at risk. Yet, a relative carrying the same gene variant as that of a diagnosed family member often does not develop the disease. Moreover, there can be a familial trend to a disease and yet, a causative gene remains elusive. Proteomics offers a complementary method of analysis. This study utilizes technology that has been developed to see molecules in their natural habitat (visual proteomics) and proposes that minute changes in their position, regardless of the genetic information, can be a sign for disease risk. Because molecular visualization is not possible with standard microscopy, this study will will look at protein clusters in three dimensions at a resolution of about 40 millions of times as small as the head of a pin. This “super-resolution” imaging will be combined with new technology to obtain, from the blood of an individual, stem cells that can be rerouted to make cardiac cells (human Induced pluripotent stem cell-derived cardiac myocytes). With this combination, the position and dimensions of molecular clusters in their natural habitat can be defined for a particular individual. The study will then explore whether these parameters are different when comparing unaffected individuals with those with an overt case of disease. Findings will improve the detection of individuals that require medical intervention based on their risk of sudden death.

Kristi Glotzbach, MD

"Influence of Pediatric Cardiomyopathy on Health Related Quality of Life"
Albert Einstein College of Medicine, Bronx, NY
2015 Amount Awarded – $50,000

Pediatric cardiomyopathy (CM) affects 1.13 in 100,000 children every year. Patients and families struggle with the disease burden, medications and procedures on a daily basis. Cardiomyopathy not only affects physical health but negatively impacts emotional health, neurodevelopment and psychosocial functioning in patients and their families. Despite these statistics and concerns, most pediatric studies focus on therapies for CM, and few address the influence of CM on patient and family quality of life (QoL). With traditional forms of research, approaching patients at one center or at multiple centers are limited by the availability of participants at each center. In the current era, patients and families are well informed about their disease, and they are using social media resources to find other families living with similar diseases and making beneficial personal connections. This study will utilize social media for patient recruitment to enroll more participants compared to traditional enrollment strategies. Patients and their caregivers will be asked to complete a survey called the Pediatric Cardiac Quality of Life Inventory (PCQLI). PCQLI scores and specific answers will identify modifiable life stressors that influence QoL and set clinical targets for improving the care of patients with CM. Families will be recruited to participate and share their experiences through Facebook and other social media sites. This research approach will establish social media as a novel and valid method of patient recruitment. Additionally, a new community will emerge for discussion amongst CM patients, families and health care providers.

Lars Gross-Wortmann, MD

"Prevalence and Evolution of Late Gadolinum Enhancement and Myocardial Hypertrophy in Childhood Cardiomyopathy"
The Hospital for Sick Children, Toronto, Canada
2015 Amount Awarded – $46,918

Hypertrophic cardiomyopathy, or HCM, is a disease in which the heart muscle is abnormally thickened. HCM is among the most common reasons for dying suddenly in children and young adults. Sudden cardiac death in these patients is often the result of an abnormal heart rhythm. Unfortunately, even if a patient is known to have HCM it is very difficult to predict whether he or she is at risk of sudden death. Many patients with HCM have no warning signs before collapsing and, in some cases, dying. From experience in adults with HCM, patients with severe thickening of the heart muscle and/or those with scars in the heart muscle tend to be at higher risk for complications. Scarring and thickening can be measured with magnetic resonance imaging, or MRI. In contrast to adults, it is not known how much muscle scarring has already occurred in children. It also is not known how the scarring and thickening progress during childhood and adolescence or whether they are linked to poor outcomes. The numbers of patients who are followed at any one center are too small to answer these questions. Therefore, this study will combine MRI data from several hospitals and look at whether pediatric patients had rhythm problems, fainting or heart failure. The goal is to determine how many children with HCM have scarring of their heart muscle and how thickened their heart is. The findings from this study will inform physicians on when to start ordering MRIs in children with HCM. Ultimately, this study’s aim is to determine whether MRI is able to identify those pediatric patients who are at risk for sudden cardiac death.

Robert Henning, MD

"Human Cord Mesenchymal Stem Cells Decrease Cardiomyopathy Fibrosis"
University of South Florida, Tampa, FL
2015 Amount Awarded – $50,000

No specific etiology has been found for the majority of children with dilated cardiomyopathy. Moreover, no consistently effective treatment exists, and consequently only 40% of children with dilated cardiomyopathy survive for five or more years. This study investigates the use of human umbilical cord blood stem cells for the treatment of dilated cardiomyopathies. Human umbilical cords, which are more readily available, contains cord blood stem cells (mesenchymal stem cells) that do not stimulate an inflammatory response in the recipient and therefore do not require suppression of the immune system. Previous studies on a TO2 hamster that served as a animal model of dilated cardiomyopathy showed that a single injection of human umbilical cord stem cells can reduce heart dilation and fibrosis and preserve heart contractility in the short term. This study will investigate the injection of human umbilical cord stem cells into TO2 hamsters at 1-4 months of age to determine the effects of these stem cells in the hearts of the hamsters at 4-12 months. The results will be compared to the effects with TO2 hamsters treated with a sodium chloride solution (salt water). The hypothesize is that human umbilical cord stem cells, when serially injected intravenously into TO2 hamsters, will migrate to the heart, limit heart dilation and fibrosis, and thereby preserve normal heart function and increase survival.

Abdur Razzaque, PhD

"Mechanism of RAF1 Mediated Pediatric Hypertrophic Cardiomyopathy"
University of Wisconsin, Madison, WI
2015 Amount Awarded – $48,000

Hypertrophic cardiomyopathy (HCM) is commonly observed in 15-25% of the pediatric patients with Noonan syndrome (NS), an autosomal dominant disorder. Previously, gain-of-function RAF1 gene mutations in NS were identified specifically in patients with HCM. It also was found that growth hormone treatment exacerbates HCM in patients with a specific RAF1 mutation (S257L). RAF1 is a mitogen-activated protein kinase that plays a central role in the signaling pathway regulating the induction of genes that determine the biological response of the cells, including cardiac hypertrophy. In vitro studies show that because of the gain-of-function activity, the RAF1 mutation dysregulates the signaling pathway that causes HCM in pediatric patients. By analyzing genetically engineered mice and using pharmacologic inhibitors, this study will 1) determine the effect of RAF1 mutation in cardiac cells and its contribution to the development of HCM, 2) determine the cellular mechanism(s) of how the RAF1 mutation leads to HCM and 3) analyze the effect of growth hormone in the hypertrophic heart. These findings will provide novel insights into the function of RAF1 and its mutations in the development of HCM in children. Understanding the exact cellular mechanism(s) caused by this gene dysfunction and the effect of growth hormone on HCM help to improve medical management and to develop new treatment strategies for pediatric HCM patients.

Timothy Wong, MD

"Cardiovascular Magnetic Resonance Assessment of Diffuse Myocardial Fibrosis in Hypertrophic Cardiomyopathy"
University of Pittsburgh
2014 to 2018 Amount Awarded (CCF/AHA Joint Research Grant) - $308,000

Improving our understanding of fundamental disease pathways, such as scar tissue (fibrosis) development in the heart, may improve our ability to understand and treat a variety of heart conditions. Current therapy for hypertrophic cardiomyopathy (HCM), a genetic heart disease, is focused on symptom relief rather than directly targeting underlying causes. Fibrosis appears to be a key disease process in HCM and is associated with adverse events, such as heart rhythm disorders, heart failure and sudden cardiac death. Previously, study of fibrosis had been limited to viewing the heart tissue under a microscope, which is not always feasible. Cardiac magnetic resonance imaging (MRI) provides a new and noninvasive way of imaging heart fibrosis. Specific new MRI methods now allow the measurement of diffuse fibrosis anywhere in the heart muscle, beyond current clinical MRI methods, which typically detect more concentrated areas of fibrosis. The Assessment of Diffuse Myocardial Fibrosis by Cardiovascular Magnetic Resonance in HCM (ADMIRE-HCM) Study plans to perform MRI heart scans in several hundred individuals with HCM to determine why some individuals have more or less fibrosis than others. Some individuals will also undergo repeat MRI scans to estimate how fibrosis changes over time. Finally, the study will characterize how fibrosis in individuals correlates with cardiovascular outcomes. Studying the role of the entire range of fibrosis in HCM disease progression may improve our understanding of the underlying pathways of the disease, identify new treatment targets and allow measurement of their response to therapy.

Daniel Bernstein, MD

"iPSC-Derived Cardiomyocytes in Left Ventricular Non-Compaction Cardiomyopathy"
Stanford University, Palo Alto, CA
2014 Amount Awarded – $50,000

Left ventricular non-compaction (LVNC) cardiomyopathy is a cause of heart failure that is increasingly being recognized in patients of all ages, but especially in children where it represents almost 10% of cases. LVNC has unique features that distinguishes it from other forms of cardiomyopathy: deep and extensive trabeculation of the left ventricle giving it a sponge-like appearance. Unlike other forms of cardiomyopathy, LVNC can present with a combination of symptoms and altered heart function, ranging from a poorly contracting heart to a heart that is stiff and resists filling, as well as life-threatening abnormal heart rhythms. LVNC has been associated with mutations in a wide variety of genes. However, the mechanisms that link a specific gene mutation to the structural and function alterations in the heart seen in LVNC are unknown. This research will use a novel technology, induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs), as a model system to study LVNC. Three families with multiple affected and non-affected members with LVNC will serve as the source for both LVNC and control iPSC-CMs. The study will (1) determine the mechanisms of structural and functional alterations in LVNC, where iPSC-CMs will be generated from LVNC and control subjects and their structure, function, growth potential and gene expression will be characterized, and (2) determine the role of altered mitochondrial function in LVNC cardiomyopathy. Mitochondria are the energy-generating source in heart muscle cells, and their function is often abnormal in patients with heart failure. The study will examine whether iPSC-CMs from LVNC subjects have alterations in mitochondrial function compared with control cells.

David Fedida, PhD

"Late INa Contributes to Diastolic Dysfunction in Hypertrophic Cardiomyopathy"
University of British Columbia, Vancouver, Canada
2014 Amount Awarded – $50,000

The proposed research aims to better understand the ionic molecular mechanisms behind diastolic dysfunction, a hallmark of hypertrophic cardiomyopathy (HCM). In patients with diastolic dysfunction, the lower chambers of the heart, the ventricles, are unable to properly relax, and they become stiff. As a result, the ventricles may not fill completely, and blood can accumulate in other parts of the body such as the lungs causing pulmonary congestion and leading to symptoms of heart failure or arrhythmias. This study will investigate increases in the so-called "late sodium current" (INa,L), which is an influx of sodium into cells during contraction of the heart that leads to an overload of calcium inside the heart cells and an inability of the heart to relax normally. This study proposes that increases in INa,L can underlie the kinds of cellular changes in the heart cells of a animal model of HCM, as well as the entire heart, which eventually contributes to diastolic dysfunction. Single cells will be isolated from normal mouse hearts and from genetically altered mice resembling human familial HCM with impaired heart relaxation. The properties of the INa,L currents will be compared in the two groups, and the parameters of heart relaxation will be compared as the INa,L current is increased or decreased. New pharmacological agents that specifically inhibit INa,L will be used to understand the causative role of INa,L in the failure of HCM hearts to relax normally. It also may provide direction towards molecular targets for HCM therapy in adults and children.

Anne M. Murphy, MD

"Translational Proteomics in Hypertrophic Cardiomyopathy"
Johns Hopkins University, Baltimore, MD
2014 Amount Awarded – $50,000

Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in young athletes. Symptoms include irregular heart rhythms, difficulty with exercise and heart failure; however some individuals who have HCM never develop symptoms. Although research has shown that HCM is primarily caused by mutations in sarcomeric genes, there are variations in how the disease manifests including age of onset, severity of hypertrophy and risk of sudden death even within a family with the same genetic mutation. One cause of HCM is when only one copy of a gene for a heart muscle motor protein is abnormal. The study will focus on measuring the exact quantity of the abnormal protein as well as the protein that is produced by the normal gene copy in heart muscle. This may help predict who might be at risk of symptoms and increased disease severity from greater amounts of abnormal protein. The results would serve as predictive biomarkers for classifying patient risk for poor outcome and lead to protective therapies for high-risk patients. Another factor that can affect how the heart pumps in HCM is how individual heart motor proteins are modified by a chemical change called phosphorylation in comparison to normal heart. Abnormal phosphorylation of troponin I is known to alter heart relaxation. This study will use a cutting edge "proteomics" technique to measure changes in phosphorylation at every site in this key protein for muscle regulation. Proteomic and phosphoproteomic studies will be performed on cardiac muscle from patients who undergo septal myectomy or transplantation. By determining how phosphorylation affects muscle function differently, new therapies may be developed to correct abnormal phosphorylation of heart muscle proteins.

Beata M. Wolska, PhD

"Pak1 as a Target for New Treatment of Hypertrophic Cardiomyopathy"
University of Illinois, Chicago, IL
2014 Amount Awarded – $50,000

There is a general lack of specific treatments for patients with familial hypertrophic (HCM) or dilated (DCM) cardiomyopathies caused by mutations in myofilament proteins, the molecular machine responsible for ejection of blood from the heart. HCM, in which the heart's cells grow in size and remodel inappropriately, is the major cause of sudden cardiac death (SCD) in young people and athletes. Often, SCD is the first manifestation of HCM. Current therapies aim only to alleviate symptoms once manifestation of the disease is recognized, which is commonly during later stages of disease progression. Based on family history and genetic screening, HCM and DCM linked to mutations in myofilament proteins can be detected early and therapy could be started before the development of the disease or shortly after the first symptoms start to develop. This study hypothesizes that timely activation of an enzyme called p21-activated kinase (Pak1) can serve as a new therapeutic tool to delay and/or reverse the development of HCM. By choosing different starting time points of treatment it can be determined what is the critical point in the development of the disease for treatments to be successful. The long-term objective of the proposed study is develop new or modified therapies for treatment of genetically-linked cardiomyopathies. The goal is to take advantage of early childhood diagnosis and to start preventative therapy before the disease develops or shortly after it starts.

Maria I. Kontaridis, PhD

"Developmental Effects of PTPN11 Mutations on Pediatric Hypertrophic Cardiomyopathy"
Beth Israel Deaconess Medical Center, Boston, MA
2013 Amount Awarded – $50,000

Mutations in PTPN11, a gene encoding an enzyme protein called SHP2, are directly responsible for hypertrophic cardiomyopathy (HCM). Mutations in SHP2 have been linked to nearly all cases of a disorder called LEOPARD Syndrome (LS), which involves HCM in more than 90% of cases. Under normal conditions, SHP2 serves as a regulatory enzyme that controls important cellular signaling events that determine whether cells continue to grow or to die. Because SHP2 plays such an important role in normal cell regulatory processes, mutations in SHP2 (such as those that cause LS) likely evoke abnormal signaling events during cardiac development that lead to the development of HCM in children. This study will determine how PTPN11 mutations disrupt heart function and cause HCM. Specifically, the study will 1) determine the effects of LS expression in important cell types present in the heart during development to assess which of these cell types contribute the most to the development of HCM in children; 2) analyze the formation of the heart structures and determine heart function in each of the LS cell types; and 3) determine the functional mechanisms of the cause of HCM in LS by assessing whether the LS mutation causes abnormal signaling events during heart development. Findings will both provide novel insights into the function of SHP2 and its mutations in the development of HCM in children and serve as a stepping stone to identifying potential therapies not only for patients with LS-associated HCM, but also for pediatric patients with other types of HCM as well.

Leslie A. Leinwand, PhD

"Pediatric Hypertrophic Cardiomyopathy Caused by Myosin Mutations"
University of Colorado, Boulder, CO
2013 Amount Awarded – $45,837

The vast majority of genes causing hypertrophic cardiomyopathy (HCM) encode proteins of the cardiac sarcomere, including the molecular motor protein, myosin heavy chain (MyHC). Greater than 300 mutations in MyHC have been described that cause HCM, dilated cardiomyopathy and skeletal myopathy. MyHC is responsible for heart function, and it is still not known what is wrong with this mutated motor protein. Currently there are only treatments for symptoms of the primary defect. While most cases of HCM have been described in adults, more recently, infants and children with unexplained cardiac hypertrophy have been studied and novel mutations have been found in sarcomeric genes. Infants and children with HCM have a much worse prognosis than adults, and 40% will die or require a cardiac transplant. It is believed that novel mutations found in the pediatric population represent a class of mutations that may share a common mechanism, and this study will test this hypothesis using a expression system developed precisely for the purposes of understanding the mechanisms underlying HCM. In this system, recombinant human cardiac myosin's bearing adult and pediatric mutations will be tested for their functional properties compared to wild type proteins. In addition, the effects of a myosin activator will be tested on these pediatric mutations. This small molecule drug has already been shown to be safe in people and to be effective in treating adults with heart failure. The advantage of this approach is that it has the potential to treat the root cause of the disease rather than downstream symptoms.

John Carter Ralphe, MD

"Human iPS Cells and ECT in the Study of Hypertrophic Cardiomyopathy"
University of Wisconsin, Madison, WI
2013 Amount Awarded – $50,000

One of the most common genetic causes of hypertrophic cardiomyopathy (HCM) involves defects in a protein called cardiac myosin binding protein C (cMyBP-C). This protein makes up part of the contractile unit within each cell of the heart muscle and participates in the regulation of muscle contraction. Exactly how some of mutations in the DNA that produces cMyBP-C lead to severe, early childhood-onset HCM is unclear. The proposed research will examine the impact of an identified HCM-causing mutation in human cells using skin fibroblasts that have been genetically reprogrammed through induced pluripotent stem cells (iPS cells) to become beating heart cells. The HCM mutation within these cells will be expressed and examined in how it affects the way the cells contract, and importantly, how the cells become dysfunctional on their way to developing hypertrophy. For the study, iPS-derived heart cells will be formed into a three-dimensional strip of muscle referred to as human engineered cardiac tissue (hECT). Using this human heart muscle test system, the study will seek to identify how environmental factors may modify, either positively or negatively, the progression of the disease. These studies will enhance our understanding of the genetic forms of HCM and provide insight into the development of more effective treatments.

Daniela Cihakova, MD, PhD

"Drivers of pediatric dilated cardiomyopathy"
Johns Hopkins University, Baltimore, MD
2012 Amount Awarded – $50,000

Dilated Cardiomyopathy (DCM) is a major cause of heart failure in children and frequently requires cardiac transplantation. Currently, no drug is available to delay or stop progression to DCM, or improve the long-term survival of children with DCM. Studying mice models of DCM can help to better understand the mechanism of DCM development. In past mouse studies, it was discovered that an immune cell product, called cytokine IL17A, is essential to the development of DCM and that mice that were deficient in that cytokine did not develop DCM. It was also found that heart cells (cardiomyocytes and cardiofibroblasts) can receive signals from IL17A with the possibility that IL17A promotes DCM by its direct action on cells in the heart. Furthermore, IL17A induces production of another cytokine Granulocyte-macrophage colony-stimulating factor (GM-CSF) in the mouse’s heart. This study proposes that IL17A induces DCM development through GM-CSF. This concept will be tested on a mouse model as well as on cardiac cells isolated from mouse hearts growing in test tube. Since DCM is often preceded by myocarditis, the study will explore whether blocking a particular cytokine such as IL17A or GM-CSF after heart inflammation could lead to arrest or improvement of the pathological changes that lead to DCM. If successful, the same strategy will be proposed for treatment of humans with DCM and could lead to the first biological treatment for DCM.

Mark K. Friedberg, MD

"Patterns and clinical significance of electro-mechanical dyssynchrony in pediatric dilated cardiomyopathy"
Hospital for Sick Children, Toronto, Canada
2012 Amount Awarded – $44,550

Dilated cardiomyopathy (DCM) is a serious illness, which can cause premature death or lead to a heart transplant. This study will identify abnormal muscle contraction in DCM to understand which children can be treated with new therapies that have helped adults with DCM. Children with DCM may have a slow spread of the heart’s electrical signal in the heart muscle causing different parts of the heart to squeeze at different times, rather than all together, thereby interfering with the heart’s ability to pump and fill with blood. Stimulating the left and right heart chambers with an electrical signal (pacemaker) to make them squeeze at the same time (cardiac resynchronization therapy, CRT) improves the heart's pumping action and has been shown to improve life quality and life expectancy in adults with heart failure. At this time, it is unknown whether CRT will help children with heart failure from DCM. In the proposed study ultrasound (sound waves) techniques will be used on 60 children with DCM to analyze the squeeze and relaxation of different parts of the heart muscle. The study will look at how abnormal heart muscle motion affects the heart’s function and whether this causes some patients to do poorly. This information will allow us to better understand which children with DCM may benefit from CRT. This study will also gather data from DCM muscle samples to investigate how different genes cause injury when the heart’s motion is abnormal.

Carmen (Kika) Sucharov, PhD

"MicroRNA expression in children with heart failure"
University of Colorado, Denver, CO
2012 Amount Awarded - $50,000

Emerging experimental evidence data suggests that the pediatric heart failure population is different from adult patients. Dilated cardiomyopathy (DCM) is the most common cause of heart failure and reason for cardiac transplantation in children. To date, a reliable profile to predict outcome for children with DCM does not exist, and pediatric cardiologists are not always able to determine the most appropriate medical treatment option for these patients. Although many children with DCM who present in acute decompensated heart failure have a poor outcome, 15-35% of children do recover from the disease. This high potential for recovery underscores the importance of defining biomarkers in children with DCM. This study will look at microRNA expression in the circulating blood of DCM pediatric patients as a possible biomarker that can determine how they will respond to heart failure at the time of disease presentation. MicroRNAs are small nucleic acids that are associated with cardiovascular disease that can be used as a diagnostic and prognostic tool. Certain microRNAs are present in circulating blood and can be associated with poor outcome in adult DCM patients. However its role in children is unknown. This study will define the circulating microRNAs in children with DCM to determine the feasibility of microRNAs as a prognostic marker for pediatric heart failure. The findings from this study have the potential to reduce the high rate of death and cardiac transplant in the pediatric DCM population.

Wendy Chung, MD, PhD

"Identification of new genes for infantile cardiomyopathy"
Columbia University, New York, NY
2011 Amount Awarded – $100,000

For infants with cardiomyopathy, it is particularly challenging to determine the cause of cardiomyopathy in a family because less is known of cardiomyopathy in infants compared to older children and adults. Identifying the cause of cardiomyopathy is particularly important for infants since their prognosis is on average worse and because families are often considering having additional children and would like to better understand the risk of having another similarly affected child. This multi-center study will be examining infants with cardiomyopathy using the most advanced genetic methods including exomesequencing in which the portion of the DNA that contains our 20,000 genes is sequenced and analyzed. Families with more than one affected infant without an identifiable genetic cause will be the focus since these families are most likely to have an underlying novel genetic basis. After sequencing the coding region of the genes, known normal genetic variants will be filtered out and disease-causing mutations in new genes for infantile cardiomyopathy will be identified. After identifying new genes for infantile cardiomyopathy, other children with cardiomyopathy will be screened for mutations in that same gene to confirm findings. Identification of new genes for infantile cardiomyopathy should help establish new targets for treatment, clarify the prognosis for families, and provide reproductive options for families to have healthy children in the future.

Steve Lipshultz, MD

"Pediatric Cardiomyopathy Registry Auxiliary Studies"
Pediatric Cardiomyopathy Registry Administrative Coordinating Center, Miami, FL
2011 Amount Awarded – $250,000

Kathy Hodgkinson, PhD

"Informing diagnostic and prognostic information for arrhythmogenic right ventricular cardiomyopathy type 5 (ARVD5) in children by comprehensive clinical and genetic analysis"
Memorial University of Newfoundland, NL, Canada
2011 Amount Awarded – $49,645

ARVC is an autosomal dominant cause of sudden cardiac death (SCD) in young people due to ventricular tachyarrhythmias, heart failure and structural anomalies of both ventricles. Many families in Newfoundland, the Eastern most province in Canada, have a genetic subtype known as ARVD5, which can cause sudden cardiac death (SCD)) due to a mutation in the TMEM43 gene. Although all adults with this mutation will show some sign of ARVD5 in their lifespan, it is not known who will develop the lethal form of the disease, what the early effects on children are and whether the prognosis can be altered by this understanding. This study will look at a homogenous population and determine how the presence of the TMEM43 mutation clinically affects those under 18 years. By studying children under 18 years in Newfoundland who have a family history of the disease and are at risk of ARVD5, it can be determined which individuals are at greater risk of negative outcomes. The study will involve following children annually with routine cardiac clinical tests and adding two additional diagnostic tests using signal averaged ECG and tissue Doppler imaging of the RV and LV outflow tract. The information from this study will have clinical significance to those families facing the effects of the disease and determining treatment.

Carmelo Milano, MD

"Expanding the Donor Pool for Pediatric Heart Transplant"
Duke University, Durham, NC
2011 Amount Awarded – $50,000

Cardiac transplantation remains the most effective treatment for children with advanced cardiomyopathy and heart failure that is refractory to medications and associated with marked functional limitation and life expectancy of less than one year. However, the shortage of available heart donors remains a problem. Conventionally, heart transplantation has utilized brain dead (BD) donors who continue to have cardiac function. Although non-cardiac organs from donation after cardiac death (DCD) are being increasingly utilized, DCD hearts are not currently being utilized. Since DCD donors suffer severe brain injury and must be declared dead after cessation of mechanical ventilation and cardiac arrest, there are concerns that ischemia and reperfusion (I/R) injury may occur during cardiopulmonary arrest. Encouraging evidence shows that DCD donors are relatively younger than BD donors making it more suitable for pediatric cardiac transplantation. Furthermore, hearts from BD donors who have experienced cardiac arrest do not portend a negative survival following transplantation. In this proposal, readily available DCD pediatric, DCD adult, and BD donor hearts will be placed on the LifeCradle™ perfusion apparatus and perfused with a solution designed to minimize I/R injury. Samples of perfusate will be tested for biomarker concentration. These hearts will be functionally assessed using a Langendorff working heart apparatus. Comparison of data from the different donor hearts will enable parameters to be developed for determination of heart quality. Ultimately, this work should lead to the development of a clinical protocol for pediatric heart transplantation utilizing a DCD donor.

Jil Tardiff, MD, PhD

"Development of a Model System for Tropomyosin-linked Early Onset Dilated Cardiomyopathy"
Albert Einstein College of Medicine, Bronx, NY
2011 Amount Awarded – $50,000

Dilated cardiomyopathy (DCM) is a very common form of cardiomyopathy and carries a particularly poor patient outcome. One of the most important observations in the field in the past decade has been that, like adults, dilated cardiomyopathy in children is often genetic in origin. Moreover, the genetic causes include mutations in known components of the cardiac sarcomere. These striking findings have led to a significant change in our view of the pathogenic mechanisms that cause DCM in children. A novel mutation in alpha-tropomyosin (D230N) a thin filament component of the sarcomere, was recently shown to cause a complex cardiomyopathy that presented in both early childhood with heart failure and sudden death and as a milder form in adults. This “bimodal” distribution of disease onset suggests that the primary DCM mechanism in childhood may change over time and suggests that the normal changes associated with cardiac growth in children are potentially involved. A better understanding of how these native changes in sarcomeric protein expression alter the disease state would provide a novel approach to developing therapies and interventions to alter the progression of this severe form of DCM. The proposed study will look at whether age-dependent changes in the cardiac forms of Troponin T, an important tropomyosin binding partner, drives the age-dependent cardiac remodeling that defines the disease. To fully investigate this hypothesis, a high-throughput in vitro screen and a novel transgenic mouse model carrying the D230N mutation will be utilized.

Bernhard Kuhn, MD

“Characterizing Molecular Mechanisms of
Cardiomyocyte Proliferation Aimed at Developing
New Regenerative Therapies of Cardiomyopathy”
Children’s Hospital Boston
2010 Amount Awarded – $50,000

The inability of human hearts to replace lost heart muscle cells predisposes victims of cardiomyopathy to the development of heart failure. Currently, the only hope for the survival of these young patients is heart transplantation, but the scarcity of suitable organs and the potential of rejection seriously limit this approach. A leading hypothesis is that advanced heart failure is effectively a cardiomyocyte (heart muscle cell) deficiency disorder, in short, that cardiomyopathy leads to loss of heart cells and hence to heart failure. Therefore, novel approaches for regenerating heart muscle by inducing proliferation of cardiomyocytes could transform the therapy for heart failure. In recent studies, it was shown that mammalian cardiomyocytes, which normally stop dividing early in life, can be induced into a proliferative state by exposure to the growth factor Neuregulin 1 (NRG1) and by periostin peptide. It was proven that these treatments enhance myocardial regeneration and improve heart function in animals. The goal of this project is to understand the molecular mechanisms that underlie cardiomyocyte proliferation after birth. Microarray technology will be used to study gene expression patterns in individual cardiomyocytes during cell cycle re-entry (proliferative state) and exit (non-proliferative state). It is anticipated that study findings will generate a list of novel candidate genes that play a role in controlling the proliferation of heart muscle cells, and in helping to improve function in diseased hearts. Future directions will involve the functional characterization of the identified genes to serve as potential biomarkers for heart disease, and/or as therapeutic targets for heart muscle regeneration, thereby reducing the enormous socioeconomic burden associated with heart transplants in children with cardiomyopathy.

J. Carter Ralphe, MD

“3D Engineered Cardiac Tissue: A Novel Tool to
Unravel Genotype/Phenotype Relationships in
MYBPC3 - Associated Childhood Hypertrophic
Cardiomyopathy”
University of Wisconsin, Madison, WI
2010 Amount Awarded – $50,000

One of the most common genetic causes of hypertrophic cardiomyopathy (HCM) involves defects in a protein called cardiac myosin binding protein C (cMyBP-C). Different mutations in the gene for cMyBP-C result in widely ranging disease severity and age of onset, with particularly severe forms presenting during infancy. Exactly how certain mutations result in childhood onset disease while others present in adulthood remains unclear. Unfortunately, as with many rare genetic diseases, the resources required to uncover the physiology of any specific mutation using traditional animal models are significant and demand an enormous time commitment. This study will focus instead on adapting a three-dimensional model of cardiac tissue made from mouse heart cells deficient in mouse cMyBP-C in which human MYBPC3 will be expressed to introduce specific HCM-causing mutations. Using this model system, abnormalities in function can be defined and the adaptive responses to the mutation that lead to hypertrophy characterized. This model should afford a rapid means to characterize mutations in important, but rare, human causes of HCM. Furthermore, by examining how specific mutations respond to physiologic stress, there will be a better understanding of why different mutations in the same protein lead to such a range in disease severity. Ultimately an improved understanding of the mechanisms behind the development of clinically significant HCM should lead to improvements in the care of children with cardiomyopathy.

Steve Lipshultz, MD, Sarah Messiah, PhD, James Wilkinson, MD

"Relationship of Growth Patterns on Outcomes for Children with Cardiomyopathy Serial Echocardiography as a Research Tool for Pediatric Cardiomyopathy Outcomes"
Pediatric Cardiomyopathy Registry Administrative Coordinating Center, Miami, FL
2008 Amount Awarded – $25,000

Stephanie Ware, MD, PHD

“Genes and Modifiers in Pediatric Cardiomyopathy”
Cincinnati Children’s Hospital, Cincinnati, OH
2010 to 2012 Amount Awarded – $86,735

An understanding of the causes of cardiomyopathy in children is less advanced than in the adult cardiomyopathy population due to fewer patients, increased genetic heterogeneity and fewer resources for research. While it is clear that genes that cause cardiomyopathy in the adult population also play a role in pediatric cardiomyopathies, their relative contribution is unclear. The long-term goal of this study is to identify the disease causing and disease associated genetic variants underlying pediatric cardiomyopathy using novel genomic technologies in patients with clinically well defined subtypes of cardiomyopathy. The study will test the hypothesis that two or more mutations account for a subset of cases characterized by early onset, severe and aggressive disease in the pediatric population. This study will further develop novel genetic testing approaches for the identification of pathogenic mutations and disease associated variants. Identifying the disease causing and disease associated genetic risk factors can greatly impact anticipatory prevention, surveillance, early management and disease course. In addition, these results will affect the development and application of the new genomic technologies in clinical medicine and will provide an intellectual framework for further investigation of the genetic basis of cardiomyopathy in children.

Jay Reddy, DVM, PhD

"Delineating Autoimmunity in Postinfectious Myocarditis"
University of Nebraska, Lincoln, NE
2009 to 2013 Amount Awarded (CCF/AHA Joint Research Grant) - $308,000

Dilated cardiomyopathy (DCM) is a leading cause of death and heart transplants in children, due to the lack of effective treatments. Viral myocarditis induced by Coxsackievirus B3 (CVB3) is a common suspect in patients with DCM and the majority of them have elevated antibody levels to CVB3, but the attempts to demonstrate infectious viral particles have largely failed. Circulating antibodies have been demonstrated in patients with DCM to various antigens, including cardiac myosin suggesting that autoimmune response is an underlying mechanism for the development of DCM. It has long been debated whether the DCM occurs as a result of viral damage or a misdirected attack by the immune system. The study will use the mouse model of viral myocarditis induced with CVB3, which has features that mimic human disease to define the role of autoimmune response to the induction of postinfectious myocarditis. It is thought that myosin-reactive T-cells (lymphocytes) are generated during CVB3 infection and contribute to chronic inflammation. To address this hypothesis, class II reagents (tetramers) will be used to determine the generation and function of cardiac myosin and CVB3-specific or their cross-reactive T cells to induce myocarditis in susceptible mice. The use of tetramers will allow us to track the generation of antigen-specific T cells by fluorescence-activated cell sorting. Since CVB3-induced disease in mice is similar to that of humans, the proposed studies will provide new insights into the occurrence of post infectious cardiomyopathy, which will lay the foundation for new therapy to be targeted toward either virus or autoimmunity.

For more information on the Children's Cardiomyopathy Foundation and American Heart Association Joint Research Grant, visit the American Heart Association site.

Charles Murry, MD, PhD

"Comparative Analysis of Human iPS Cells to Generate Vascularized Cardiac Tissue Constructs"
University of Washington, Seattle, WA
2009 Amount Awarded - $50,000

Most pediatric hyperthrophic cardiomyopathies and many dilated cardiomyopathies have a genetic basis, and the only definitive treatment is cardiac transplantation, which is limited by organ availability. Stem cells provide a novel source of cardiomyocytes that can be transplanted to repair the cardiomyopathic heart. Embryonic stem (ES) cells can robustly generate cardiomyocytes, and transplanting ES cell-derived human cardiomyocytes prevents heart failure in cardiac injury models. However, ES cells are ethically controversial and may face immune rejection. Cellular reprogramming of adult fibroblasts to "induced pluripotent stem (iPS) cell" state has the ability to differentiate into many different cell types and potentially removes the immune barriers for transplantation. The long term goals of this study are to derive iPS cells from pediatric cardiomyopathy patients with defined mutations, and then use iPS cell-derived cardiomyocytes to understand cardiomyopathy, screen new drugs for its treatment, and to develop genetic correction strategies using homologous recombination. The study will first characterize the cardiovascular differentiation potential of three different human iPS cell lines. This will involve directing the differentiation of iPS cells to cardiomyocytes and endothelium using protocols established for human ES cells, and comparing yields, purities and gene expression patterns of the resulting cardiovascular cells to results from well-characterized human ES cell lines. Then human iPS cell-derived cardiomyocytes and vascular cells will be used to generate 3-dimensional tissue engineered constructs of vascularized human myocardium that can be used for assessing contractile function and potentially for therapeutic applications. These studies will form the basis for derivation of cardiovascular cells from patients with pediatric cardiomyopathy, shedding light on disease mechanisms and possibly establishing a novel therapeutic platform.

George Porter, MD

"Calcium Channel Disruption: A New Model of Non-Compaction Cardiomyopathy"
Yale University, New Haven, CT
2008 to 2010 Amount Awarded (CCF/AHA Joint Research Grant) -$198,000

Non-compaction cardiomyopathy accounts for up to 13% of all clinically recognized childhood cardiomyopathies. The clinical spectrum of this disease is quite broad, with some patients presenting with heart failure while others never develop symptoms. This suggests that non-compaction is the result of an arrest of heart muscle development, and that the wide range of presentations is due to varying degrees of this disruption. While it is known that certain genetic mutations give rise to non-compaction, the mechanism by which non-compaction cardiomyopathy occurs remain unclear. In past studies, it has been found that deleting the major calcium channel in the heart to disrupt normal calcium levels causes non-compaction cardiomyopathy in the embryo. It is believed that abnormal calcium channel function leads to abnormal ventricular myocardial organization, leading to non-compaction. Using a mouse model, this study will first characterize when and how non-compaction develops and then study the mechanism of normal myocardial development and determine how abnormalities in this process can lead to non-compaction cardiomyopathy. These results may ultimately lead to clinical studies into the origins, diagnosis, and treatment of non-compaction cardiomyopathy. It may also further and guide genetic testing, risk assessment, and reproductive counseling for patients with this form of cardiomyopathy.

For more information on the Children's Cardiomyopathy Foundation and American Heart Association Joint Research Grant, visit the American Heart Association site.

Stephanie Ware,
MD, PhD
"Development of a Novel Resequencing Chip to Diagnose Pediatric Cardiomyopathy"
Cincinnati Children's Hospital, Cincinnati, OH
2008 Amount Awarded - $49,750

Cardiomyopathy is a heart muscle disorder that can be caused by mutations in genes which produce proteins necessary for heart function. While significant progress has been made in identifying the genetic basis of cardiomyopathy in adults, molecular diagnosis in children has proven more challenging. Recent studies indicate that a child's outcome depends on the underlying cause of cardiomyopathy, highlighting the importance of making a precise diagnosis. However, lack of accurate and cost-effective methods for analyzing multiple genes has limited the ability to investigate and precisely diagnose pediatric cardiomyopathy. The goal of this study is to develop and validate a novel resequencing gene chip for the diagnosis of pediatric cardiomyopathy. This new technology allows comprehensive and simultaneous analysis of multiple genes, thereby avoiding many of the historical diagnostic problems. A customized gene chip will be developed to include 30 proteins known to cause cardiomyopathy. It will include the most common genetic causes of cardiomyopathy in adults as well as the genetic causes for metabolic cardiomyopathy, a frequent but relatively uninvestigated cause of cardiomyopathy in children. Since limited genetic studies have been performed in the pediatric population, a second anticipated and important outcome of this study is to determine mutation prevalence in a carefully selected group of pediatric patients. In the first phase of the study, 20 patient DNA samples with known genetic causes of cardiomyopathy will be used to test and validate the gene chip. In the second phase, DNA from 40 patients with a diagnosed mitochondrial disorder and 40 patients with idiopathic cardiomyopathy will be analyzed. This study will give important information about the type and rate of gene mutations in children with cardiomyopathy. Development of novel diagnostic technology will allow for rapid, efficient, and cost-effective detection of genetic causes of cardiomyopathy, which will help management and the development of new treatment strategies.

Enkhsaikhan Purevjav,
MD, PhD
"Effects of ACE Inhibitors and Beta-blockers on Cardiac Function in Murine Models of Inherited Dilated Cardiomyopathy due to Mutations in the Nebulette Gene"
Baylor College of Medicine, Houston, TX
2008 Amount Awarded - $45,000

Dilated cardiomyopathy (DCM) is a serious disease of the heart muscle leading to congestive heart failure (CHF). Patients with CHF at the time of DCM diagnosis have a 4-fold hazard of death or transplantation in the first year after diagnosis compared to those without CHF. Therefore, early diagnosis and treatment of the "at risk" DCM population at the preclinical stages is crucial. The goal of this study is to find better ways to improve the clinical management and treatment of patients with DCM at the earliest stages of the disease. Classic cardiovascular therapy agents, such as, beta-adrenergic blockers and angiotensin converting enzyme (ACE) inhibitors are known to increase left ventricular function and reduce cardiac mortality in patients with CHF. This study will investigate the individual and combined effects of administering two common therapeutic agents, carvedilol (beta-blocker) and captopril (ACE inhibitor), during the preclinical and clinical stages of DCM in animal models with inherited DCM. The transgenic mice being studied carry human mutations in the nebulette gene. Cardiac function will be monitored during treatment. Then, to delineate the molecular mechanisms of carvedilol and/or captopril therapy, the mice hearts will be analyzed by histological, immunochemical, ultrastructural and protein analyses. This study will thus provide insight into the molecular mechanisms of the preventative and therapeutic effects of ACE inhibitors and beta-blockers on inherited human DCM.

Bruce D. Gelb, MD
"Hypertrophic Cardiomyopathy and RAS-MAP Kinase Signaling"
Mount Sinai School of Medicine, New York, NY
2008 Amount Awarded - $49,587

Hypertrophic cardiomyopathy, the condition in which there is an excess of heart muscle, is a serious cardiac condition that can lead to illness and death. In adults, most cases are caused by mutations in genes for the structural protein in heart muscle cells. In infants and younger children, the causes are different with a genetic condition called Noonan syndrome predominating after infancy. The principal investigator's group recently identified a new gene for Noonan Syndrome in which children with mutations in this gene, called RAF1, are highly likely to develop hypertrophic cardiomyopathy. This proposal includes two sets of studies aimed at understanding how RAF1 mutations cause hypertrophic cardiomyopathy as a steppingstone to the development of novel treatments to prevent or ameliorate it. The first goal will be to introduce a mutation into the Raf1 gene in mice. This is likely to replicate the human disease and permit studies of the heart as it hypertrophies. The second goal will be to introduce mutant RAF1 genes into rat heart muscle cells in cell culture. Again, this is likely to engender cardiac hypertrophy that can be characterized biochemically. Taken together, the proposed work will provide new insights into the manner in which certain RAF1 mutations result in cardiac hypertrophy. Aside from its relevance to children with Noonan syndrome, this work will have broader impact on our understanding of how the heart responds to certain hypertrophic stimuli normally or pathologically.

Monte S. Willis, MD, PhD
"The Role of MuRF1 in MyBP-c Turnover and Its Effects on Cardiac Energy Metabolism in Familial Hypertrophic Cardiomyopathy"
University of North Carolina, Chapel Hill, NC
2008 Amount Awarded - $50,000

Familial hypertrophic cardiomyopathies (FHC) are the most common underlying cause of sudden death in children and young adults, which result from mutations primarily in proteins responsible for heart contraction. It has been identified that the cardiac specific protein MuRF1 (Muscle Ring Finger-1), mediates the degradation of one of these proteins, the cardiac Myosin Binding Protein-C (cMyBP-c). Since cMyBP-c is the most commonly mutated protein in patients with FHC, and cMyBP-c is degraded very rapidly by heart cells in these patients, this study proposes that MuRF1 may be a key regulator of this degradation as a mechanism to clear damaged proteins. Moreover, it has been identified that MURF1 regulates the turnover of proteins that transport energy (ATP) throughout the cell, and that MuRF1 inhibits increases in muscle size (cardiomyocyte hypertrophy). Therefore, the assumption is that MuRF1 is a unifying mechanism for the major underlying defects in FHC. The intent of this study is to show that in the presence of mutant cMyBP-c, MuRF1 preferentially recognizes and degrades these proteins because it identifies them as defective. When the heart mainly creates defective cMyBP-c (as in FHC), cardiac MuRF1 spends all its time clearing the mutant protein. The cost of this constant clearance is that MuRF1 is not available to regulate the heart size, or energy transport, which would explain the enlarged (hypertrophic) hearts in FHC, and the energy deficits identified in FHC patients. By identifying that MuRF1 mediates these multiple defects in FHCs, targeting and enhancing MuRF1 activity may specifically improve outcomes in patients with FHC.

Tain-Yen Hsia, MD
"Extracellular Mechanisms in Pediatric Cardiomyopathy"
Medical University of South Carolina, Charleston, SC
2007 Amount Awarded - $50,000

The extracellular matrix is an integral part of the heart. It provides the scaffolding upon which the cells of the heart can build healthy architecture and structure that are essential for normal heart functions. Abnormal maintenance of the extracellular matrix has been known to result in clinical manifestations of various forms of heart failure in adults but little is known about it's effect on children. In the heart, the regulation of extracellular matrix belongs to a set of enzymes called matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). Maintaining a delicate balance between these two groups of enzymes controls the extracelluar matrix content and thus heart function. The goal of this pilot study is to better understand the role that MMPs and TIMPs play in various pediatric cardiomyopathies, to examine differences from adult cardiomyopathy, and to develop a way to measure these enzymes from small blood samples. As a pilot study, we will focus our initial efforts on the elucidation of the role of extracellular matrix in idiopathic dilated cardiomyopathy by examining the tissue and serum MMPs and TIMP in children afflicted with this disease through biopsies, explanted heart, and stored samples in the Pediatric Cardiomyopathy Registry/Repository. By showing a direct relationship between heart failure severity and MMP and TIMP enzyme levels, biomarkers can be identified to predict the advent of heart failure and the progression of the disease, perhaps even before symptoms appear. If this methodology is proven safe and efficacious in infants and small children, it can be used to screen patients from high-risk families or backgrounds. New drugs that can modulate the extracellular matrix by re-balancing the MMP and TIMP system may be developed to prevent or improve symptoms of end stage heart failure.

This study was featured in an oral presentation, "Differential Expression in the Determinants of Extracellular Matrix Remodeling in Pediatric and Adult Dilated Cardiomyopathy," at the 2008 American Heart Association Scientific Sessions.

Anne I. Dipchand, MD
"Outcome of pediatric patients with cardiomyopathy: a multi-centre review of pediatric patients listed for transplant in the Pediatric Heart Transplant Study"
Hospital for Sick Children, Toronto, Canada
2007 Amount Awarded - $42,642

Although the treatment of heart failure due to all types of cardiomyopathy in children continues to improve, a certain number of children continue to go on to need a heart transplant. Currently, there is limited information on how to predict when these children should be listed for a heart transplant and what things might make them more or less likely to survive a heart transplant. Listing for a heart transplant too early or too late is detrimental for the patients involved. Because there is very little clinical information available, there is great variability on the criteria that physicians and hospitals use to make decisions about the need for and the timing of listing for a heart transplant. This research study will utilize clinical data from the Pediatric Heart Transplant Study Group (PHTSG) collected from children with cardiomyopathy who were then listed for a heart transplant (over 1,100 patients). This project proposes to describe what happens to children with cardiomyopathy once they get listed for heart transplantation and will provide a more in depth analysis of heart transplantation as a treatment for children with cardiomyopathy. By analyzing the PHTSG information on patients with cardiomyopathy, we can determine what factors make them more likely to need a heart transplant and to survive, the optimal time of listing for a heart transplant, and how they do post transplant from a quality of life standpoint. It will also allow us to look for differences based on factors such as age, sex, type of cardiomyopathy, and treatments. The information learned from such a large group of patients will almost certainly be important for the clinical management of and future studies in children with cardiomyopathy.

This study was featured in an oral presentation, "Outcomes of Children with Cardiomyopathy Listed for Heart Transplant: A Multi-Institutional Study," at the 2007 American Heart Association Scientific Sessions. It also lead to 2 poster presentations, "Dilated Cardiomyopathy and Listing for Heart Transplantation," and "Outcomes of Children with Restrictive Cardiomyopathy Listed for Heart Transplant," and an oral presentation, "Outcomes of Pediatric Patients with Hypertrophic Cardiomyopathy Listed for Transplant," at the 2008 International Society of Heart and Lung Transplant Annual Meeting.

Jeffrey A. Towbin, MD
"Identification of Mutations in Genes Associated with Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy"
Baylor College of Medicine, Houston, TX
2006 Amount Awarded - $92,250

A critical issue with cardiomyopathy in children is that a high percentage of the causative genes remain unknown and the mechanisms responsible for the phenotypes and the modifiers of disease severity are also poorly understood. The two key objectives of this research is to identify the genes responsible for the clinical phenotypes in children with cardiomyopathies, and 2) define the causative mechanisms involved in the development and maintenance of childhood cardiomyopathy. Using DNA sequencing, two hundred children will be screened for the 11 most common HCM genes and the 9 most common DCM genes. By obtaining cross -sectional data that identifies the type and location of mutations associated with pediatric cardiomyopathy, the study will be able to determine the applicability of adult data to pediatric patients, identify appropriate direction for new molecular work in children, and clarify the genotype-phenotype relationship. The study will also help physicians understand the role of genetic testing in evaluating patients with cardiomyopathy and provide guidelines for testing based on patient-specific characteristics.

This study resulted in two published scientific papers, "Shared Genetic Cause of Cardiac Hypertrophy in Children and Adults" (New England Journal of Medicine, May 2008) and "Molecular Mechanisms of Pediatric Cardiomyopathies and New Targeted Therapies" (Progress in Pediatrics, April 2008).

Tracie Miller, MD
"Exercise Intervention in a Pediatric Population with Cardiomyopathy"
University of Miami, Miami, FL
2006 Amount Awarded - $45,000

It has been shown in adults with heart failure that the addition of an exercise program can improve their physical capacity. However, there is a lack of research regarding the effect of exercise (aerobic or resistance training) in children with cardiomyopathy and the molecular mechanisms related to detraining or improvements with exercise. This study will evaluate the benefit of a structured exercise program in children with cardiomyopathy. The study will recruit 20 children age 9-18 years with primary dilated cardiomyopathy and 20 healthy children to participate in a 12 week (twice a week) hospital-based aerobic and resistance training program. Children will undergo baseline studies of cardiac function through echocardiography, metabolic stress testing, Holter monitoring, evaluation of body composition, assessment of strength and flexibility, surveys to access quality of life, and comparisons of the mitochondria function and the amount of mutations. If this study proves that supervised exercise regimens can improve cardiac function, body composition and quality of life for children with cardiomyopathy the results will serve to support further studies on cardiac rehabilitation in this group. Furthermore it will elucidate molecular and biological mechanisms underlying these improvements. The findings from this research could ultimately lead to third party payer (health insurers) support for exercise training in children with cardiomyopathy.

This study resulted in a published manuscript, "Exercise Rehabilitation in Pediatric Cardiomyopathy" (Progress in Pediatrics, April 2008).

Ju Chen, PhD
"Involvement of Cypher Specific Isoforms in Dilated Cardiomyopathy"
University of California, San Diego, CA
2005 Amount Awarded - $50,000

Dilated cardiomyopathy (DCM), characterized by left ventricular dilation and systolic dysfunction with signs of heart failure, is genetically transmitted in 30-40% of cases. Genetic heterogeneity has been identified, with mutations in a number of cytoskeletal and sarcomeric genes causing a DCM phenotype. Specific mutations in the cytoskeletal protein cypher have recently been found in a large proportion of cases of dilated cardiomyopathy in children and adults. Two of the mutations, which have been characterized, are located within the same region (exon 6) of the cypher gene. The goals of this study are to generate three mouse lines, which will be models for these human mutations, and to perform preliminary characterization of them. One mouse line will have a deletion in exon 6 of cypher, and the others will have specific point mutations within exon 6 which are found in human patients. The objective will be to utilize these mouse models to model human disease and to gain an understanding of the biochemical pathways leading to cardiomyopathy. A basic understanding of these pathways will suggest therapeutic targets for cardiomyopathy and consequently heart failure.

This study resulted in three published scientific papers: “Cardiac-specific Ablation of Cypher leads to a Severe Form of Dilated Cardiomyopathy with Premature Death" (Human Molecular Genetics, November 2008),"Mouse Models for Cardiomyopathy Research" (Progress in Pediatric Cardiology, November 2007) and "Zeroing in on the Role of Cypher in Striated Muscle Function, Signaling and Human Disease" (Trends in Cardiovascular Medicine, November 2007). Results from this study lead to a five year $1.25 million research grant from the National Heart, Lung and Blood Institute.

Gerald F. Cox, MD, PhD
"Analysis of Sarcomere Gene Mutations in Pediatric Hypertrophic Cardiomyopathy"
Children's Hospital, Boston, MA
2005 Amount Awarded - $60,000

The purpose of this study is to determine whether sarcomere gene mutations are a common cause of hypertrophic cardiomyopathy (HCM) in children, and if so, how they influence the disease. In adults, HCM can be caused by mutations in 10 different genes encoding sarcomeric proteins of the contractile apparatus, which allows the heart to pump blood. In children, however, the causes of HCM are poorly understood and more varied. This study will recruit 50 subjects with HCM from the Pediatric Cardiomyopathy Registry, with approximately equal numbers diagnosed in infancy or later (2 to 18 years) and equal numbers with or without a family history of HCM. The coding regions of 8 sarcomeric genes (MHC, MBP, TNNT2, TNNI3, TTN1, alpha-actin, MLC2, and MLC3) will be fully sequenced in all patients to identify possible mutations. The study will attempt to answer the following questions: is the earlier age of onset of HCM in children compared to adults due to the presence of two mutations, different frequencies of involved genes, or other mutations in the same genes? Do the mutations correlate with clinical features and echocardiographic findings? Does HCM caused by sarcomeric gene mutations differ from HCM related to other causes? These results may help decide which children with HCM should undergo testing for sarcomere gene mutations and how the testing should be carried out.

This study was featured in an oral presentation, "Predictors of Etiology in Pediatric Cardiomyopathy," at the 2004 American Heart Association Scientific Sessions. It also lead to a published manuscript: "Factors Associated with Establishing a Causal Diagnosis for Children with Cardiomyopathy" (Pediatrics, Oct 2006).

Seema Mital, MD, FACC
"RAAS Gene Polymorphisms Influence Cardiac Remodeling in Children with Hypertrophic Cardiomyopathy"
Children's Hospital of New York-Presybyterian, New York, NY
2004 Amount Awarded - $25,000

The body produces several hormones that help to maintain blood pressure e.g. angiotensin, aldosterone. When produced in excessive amounts, these can act directly on heart muscle and cause it to thicken and lead to heart to fail over time. The production of these hormones are controlled by several genes. Variations in these genes called polymorphisms can increase the production of these hormones. This study investigates if children with hypertrophic cardiomyopathy (HCM) who have more of these polymorphisms are at higher risk for the disease becoming severe compared to children with fewer of these polymorphisms. 23 children with HCM will be studied and heart muscle thickness will be measured using echocardiography i.e. ultrasound of the heart, at each visit. The goal of the study is to show that the heart gets thicker much faster in children with more than two polymorphisms compared to those with less than two polymorphisms. The significance is that physicians will be able to identify which children with HCM are at higher risk for getting a severe form of the disease and therefore require closer monitoring. It may also help to segment which family members with the same disease are likely to do better or worse depending on the number of these polymorphisms. In many cases, it may be possible to adjust treatment according to these polymorphisms enabling physicians to better manage children with this disease in the long term.

This study was featured in an oral presentation, "RAAS Gene Polymorphisms Influence Progression of Pediatric Hypertrophic Cardiomyopathy," at the 2004 American Heart Association Scientific Sessions and published in Human Genetics, December 2007. Two additional poster and oral presentations,"Effect of Bi-Ventricular Unloading on Pathways of Myocardial Recovery in Failing Left and RIght Ventricles" and "Adrenergic Receptor Polymorphisms Influence Progression of Dilated Cardiomyopathy in Children" took place at the 2005 American Heart Association Scientific Sessions.

Steve Lipshultz, MD
"Baseline Predictors of Outcome in Children with Cardiomyopathy"
Pediatric Cardiomyopathy Registry Administrative Coordinating Center, Rochester, NY
2003 Amount Awarded - $30,000

The Pediatric Cardiomyopathy Registry was established to describe the epidemiologic features and clinical course of selected cardiomyopathies in patients aged 18 years or younger and to promote the development of etiology-specific treatments. The National Heart, Lung and Blood Institute funded registry consists of prospective, population-based cohort of patients from 100 medical centers in North America. The goal of this multi-part study is to help define what factors may be most useful in determining the course of the disease in children presenting with cardiomyopathy. Analysis of national clinical factors will allow providers the ability to predict which children will remain stable, improve or have resolution of their cardiomyopathy over time. Another endeavor will utilize the pediatric cardiomyopathy registry database to determine the role of family history at diagnosis and during medical management to predict outcomes in mortality, late abnormalities of ventricular structure and function, congestive heart failure, listing of cardiac transplantation, and/or success of receiving a cardiac transplantation.

This study was featured in 3 oral presentations and a poster presentation at the 2004 American Heart Association Scientific Session: "Incidence and Etiology of Dilated Cardiomyopathy in Children," Jeff A. Towbin, MD; "Outcome Predictors in Pediatric Hypertrophic Cardiomyopathy," Steven E. Lipshultz, MD; "Etiology-Specific Outcomes in Pediatric Hypertrophic Cardiomyopathy," Steven D. Colan, MD and "Impaired Functional Status in Children with Cardiomyopathy: A Report from the Pediatric Cardiomyopathy Registry," Lynn Sleeper, ScD.

This study resulted in three published scientific papers: "Factors Associated with Establishing a Causal Diagnosis for Children with Cardiomyopathy" (Pediatrics, October 2006), "Incidence, Causes and Outcomes of Dilated Cardiomyopathy in Children: Findings from the Pediatric Cardiomyopathy Registry" (Journal of American Medical Association, October 2006), and Epidemiology and Cause-Specific Outcome of Hypertrophic Cardiomyopathy in Children: Findings from the Pediatric Cardiomyopathy Registry" (Circulation, February 2007).

Wendy Chung, MD, PhD
"Molecular Genetic Stratification of Familial Hypertrophic Cardiomyopathy"
Columbia University, New York, NY
2002 Amount Awarded - $45,000

Familial hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disease, and the clinical course and prognosis vary according to the gene and specific mutation involved. Identification of the genetic basis would be useful in patient management and predicting other pre-symptomatic susceptible individuals within families. Because of the large number of different genes involved in familial HCM, genetic testing for this condition is expensive and not currently clinically available. The goal of this study was to develop a method for efficiently and cost effectively determining the genetic basis of HCM in families through linkage analysis and then direct mutations identification. This would also allow us to stratify an individual's risk of heart failure and arrhythmia, to potentially identify pre-symptomatic individuals and to develop individualized methods of clinical surveillance and management. This strategy would be particularly important in rare families in which there is a high risk of sudden death before there is evidence of hypertrophy on echocardiogram.

This study was featured in an oral presentation, "Strategy for Molecular Genetic Stratification of Familial Hypertrophic Cardiomyopathy," at the 2004 American College of Cardiology Scientific Session and 2004 Eastern Society for Pediatric Research Conference.

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