Left ventricular non-compaction (LVNC) cardiomyopathy is increasingly being recognized as a cause of heart failure in patients of all ages. LVNC has a unique phenotype that distinguishes it from dilated or hypertrophic cardiomyopathies: deep hypertrabeculation of the left ventricle. Unlike other forms of cardiomyopathy, LVNC commonly presents with a combination of both systolic and diastolic dysfunction, as well as with ventricular arrhythmias, mural thrombi and thromboembolism. Similar to other cardiomyopathies, LVNC has been associated with mutations in multiple cytoskeletal, sarcomeric, mitochondrial and ion channel genes. However, in contrast to the extensive data available for dilated and hypertrophic cardiomyopathies, the mechanistic basis for LVNC is still largely unknown and even the basic physiologic alterations are still largely undefined. Genetically altered murine models of "hypertrabeculation" all have other congenital heart defects and high embryonic lethality so that good model systems do not exist. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from patients with LVNC thus represent a unique opportunity to define the cardiomyocyte-autonomous phenotype and elucidate potential mechanisms, as has been recently accomplished with patient-specific iPSC-CMs for Long QT syndrome, LEOPARD syndrome and Timothy syndrome. Two families with multiple affected members with LVNC will serve as the source for both LVNC and control iPSCs derived from dermal fibroblasts. We hypothesize that iPSC-CMs derived from LVNC patients will reproduce key aspects of the disease phenotype, including alterations in systolic and diastolic function, increased arrhythmogenicity, and altered biomechanical properties and serve as a platform for elucidation of LVNC mechanisms. We also hypothesize that alterations in mitochondrial function represent one of the mechanisms for LVNC cardiac dysfunction.
Aim 1 will determine the mechanisms of structural and functional alterations in LVNC. We will generate iPSC-CMs derived from LVNC and control subjects, characterize their morphologic, electrophysiologic and biomechanical phenotype, and screen phenotype-specific modulators of cell remodeling, calcium handling, and contractile function as candidates for disease mechanism.
Aim 2 will determine the role of altered mitochondrial function and mitochondrial dynamics in LVNC cardiomyopathy. This study will serve as an excellent training platform for me to obtain training in both the conceptual framework and techniques of stem cell biology, and further my two long-term career goals: first to utilize patient-specific iPSC-CMs as a tool to increase our understanding of the molecular and cellular basis of pediatric cardiovascular disease;second, so that I can play a role in the exciting early stages of the field of stem cell therapeutics for heart failure. With th support of this training program I will be in a unique position, as one of the few pediatric cardiologists in this area, to adapt these therapies for the specific circumstances leading to heart failure in infants and children.
PROJECT DESCRIPTION AND RELEVANCE Heart failure is a leading cause of death and disability, both in adults and children. An increasingly recognized cause of heart failure is left ventricular non-compaction (LVNC) cardiomyopathy, representing up to 10% of pediatric cases. LVNC has several unique features that distinguish it from other forms of cardiomyopathies. However, in contrast to extensive research in these other cardiomyopathies, the causative mechanisms for LVNC are still largely unknown, as animal models faithfully reproducing the human disease do not exist. A novel technology has recently been developed allowing the generation of stem cells from skin biopsies obtained from patients with LVNC, and genetically manipulating them to develop into heart muscle cells. These cells will form the basis for solving the unknown mechanisms of LVNC and provide a platform to develop new methods for diagnosis and treatment.
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