Children's Cardiomyopathy Foundation
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RESEARCH

AWARDED GRANTS

Bernhard Kuhn, MD

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

Stephanie Ware, MD, PHD

“Genes and Modifiers in Pediatric Cardiomyopathy”
Cincinnati Children’s Hospital, Cincinnati, OH
Amount Awarded – 2010 to 2012: $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, NB
Amount Awarded (CCF/AHA Joint Research Grant) - 2009 to 2013: $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
Amount Awarded - 2009: $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
Amount Awarded (CCF/AHA Joint Research Grant) - 2008 to 2010: $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
Amount Awarded - 2008: $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
Amount Awarded - 2008: $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
Amount Awarded - 2008: $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
Amount Awarded - 2008: $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
Amount Awarded - 2007: $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
Amount Awarded - 2007: $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
Amount Awarded - 2006: $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
Amount Awarded - 2006: $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
Amount Awarded - 2005: $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
Amount Awarded - 2005: $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
Amount Awarded - 2004: $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
Amount Awarded - 2003: $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
Amount Awarded - 2002: $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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