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.

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 as an oral presentation at the American Heart Association Scientific Sessions, 2007 and at the International Society of Heart and Lung Transplant Annual Meeting, 2008.

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.

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.

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 two published scientific papers: "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.

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 as an oral presentation at the American Heart Association Scientific Sessions, 2004. This study resulted in the publication of "RAAS Gene Polymorphisms Influence Progression of Pediatric Hypertrophic Cardiomyopathy" (Human Genetics, December 2007). Additional published abstracts include: "RAAS Gene Polymorphisms Influence Cardiac Remolding in Children with Hypertrophic Cardiomyopathy" (Circulation 2004), "Effect of Bi-ventricular Unloading on Pathways of Myocardial Recovery in Failing Left and Right Ventricles" (Circulation 2004), and "Adrenergic Receptor Polymorphisms Influence Progression of Dilated Cardiomyopathy in Children" (Circulation 2005).

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 1 poster presentation at the American Heart Association Scientific Session, 2004: 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 - 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, January 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 as an oral presentation at the American College of Cardiology Scientific Session, 2004 and Eastern Society for Pediatric Research, 2004.