RESUMO
Inherited cardiomyopathies are among the major causes of heart failure and associated with significant mortality and morbidity. Currently, over 70 genes have been linked to the etiology of various forms of cardiomyopathy, some of which are X-linked. Due to the lack of appropriate cell and animal models, it has been difficult to model these X-linked cardiomyopathies. With the advancement of induced pluripotent stem cell (iPSC) technology, the ability to generate iPSC lines from patients with X-linked cardiomyopathy has facilitated in vitro modelling and drug testing for the condition. Nonetheless, due to the mosaicism of the X-chromosome inactivation, disease phenotypes of X-linked cardiomyopathy in heterozygous females are also usually more heterogeneous, with a broad spectrum of presentation. Recent advancements in iPSC procedures have enabled the isolation of cells with different lyonisation to generate isogenic disease and control cell lines. In this review, we will summarise the current strategies and examples of using an iPSC-based model to study different types of X-linked cardiomyopathy. The potential application of isogenic iPSC lines derived from a female patient with heterozygous Danon disease and drug screening will be demonstrated by our preliminary data. The limitations of an iPSC-derived cardiomyocyte-based platform will also be addressed.
Assuntos
Genes Ligados ao Cromossomo X , Doença de Depósito de Glicogênio Tipo IIb/genética , Doença de Depósito de Glicogênio Tipo IIb/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Diferenciação Celular , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Doença de Depósito de Glicogênio Tipo IIb/classificação , Doença de Depósito de Glicogênio Tipo IIb/patologia , Heterozigoto , Humanos , Masculino , Mosaicismo , Inativação do Cromossomo XRESUMO
BACKGROUND: Danon disease is a rare X-linked storage disorder characterized by hypertrophic cardiomyopathy leading to arrhythmias and heart failure. A preexcitation pattern on electrocardiogram (ECG) has been described in these patients, however, invasive studies to distinguish between Wolff-Parkinson-White syndrome syndrome and fasciculoventricular pathways (FVP) are limited. OBJECTIVES: The purpose of this study was to delineate the electrophysiological cardiac abnormalities in patients with Danon disease and to describe the presence of FVP in this population. METHODS: We performed a retrospective study of all patients with a confirmed diagnosis of Danon disease presenting to a single center from May 2005 to May 2018. Baseline demographics, clinical characteristics, ECG findings, and electrophysiology study (EPS) results were collected. RESULTS: Ten patients with Danon disease (30% male, average age 17.4 years) were identified. Seven patients (70%) had tachyarrhythmias including five with atrial arrhythmias and six with nonsustained ventricular tachycardia. Preexcitation pattern on ECG was found in four (40%) patients. Of these, two underwent an EPS which confirmed the presence of an FVP. One patient underwent an adenosine challenge which supported a FVP. Implantable cardioverter defibrillator was placed in five patients for primary prevention with no patients receiving an appropriate discharge. Over a follow-up of 5.3 years, five underwent heart transplantation. CONCLUSIONS: This study reports a high incidence of FVP in patients with Danon disease and preexcitation. It underscores an alternate etiology of preexcitation in this population which can potentially be diagnosed without invasive EPS testing. Future multicenter studies are needed to expand this experience.