RESUMEN
BACKGROUND: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. METHODS: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. RESULTS: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. CONCLUSIONS: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.
Asunto(s)
Síndrome del Corazón Izquierdo Hipoplásico/genética , Organogénesis/genética , Heterogeneidad Genética , HumanosAsunto(s)
Arritmias Cardíacas/fisiopatología , Células Madre Pluripotentes Inducidas/fisiología , Miocitos Cardíacos/fisiología , Imagen de Colorante Sensible al Voltaje/métodos , Potenciales de Acción/fisiología , Antiarrítmicos/farmacología , Estudios de Casos y Controles , Cisaprida/farmacología , Evaluación de Medicamentos/métodos , Humanos , Ivabradina/farmacología , Síndrome de QT Prolongado/fisiopatología , Proteínas Luminiscentes/metabolismo , Modelos Cardiovasculares , Miocitos Cardíacos/metabolismo , Bloqueadores de los Canales de Potasio/farmacologíaRESUMEN
INTRODUCTION: Human herpesvirus-8-associated B-cell lymphoma is a common disease entity in immunocompromised individuals, particularly in patients with chronic HIV-infection or AIDS. However, cardiac manifestations are extremely rare. Tissue for histopathology of left cardiac tumours is most commonly obtained by open surgery. CASE PRESENTATION: In this report, we present a case of a solitary left atrial manifestation of an HHV8+ B-cell lymphoma in a 59-year-old patient presenting with B symptoms and a cardiac mass on echocardiography. Due to the high operative risk of the patient, a transcatheter/trans-septal biopsy was performed to establish the diagnosis. DISCUSSION: In the era of routine trans-septal catheter interventions, this approach may represent a straight-forward, minimally invasive alternative for patients at high risk for surgery.