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Multiscale characterization of cardiac remodeling induced by intrauterine growth restriction, at organ, cellular and subcellular level

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Universitat de Barcelona. Facultat de Medicina

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[spa] INTRODUCCIÓN: La restricción de crecimiento intrauterino (CIR) debido a insuficiencia placentaria afecta a un 7-10% de las gestaciones y constituye la mayor causa de mortalidad perinatal i morbilidad a largo plazo. El CIR resulta en bajo peso al nacer, lo que se relaciona con un incremento de la mortalidad por causas cardiovasculares en edad adulta, y se cree que está mediado por el concepto de “programación fetal” de la función cardiovascular. HIPÓTESIS: El CIR induce un remodelado cardiaco acompañado de disfunción cardiaca, a nivel del órgano, célula y orgánulo. OBJETIVOS: Caracterización del remodelado y función cardiaca en el CIR, a nivel de órgano, célula y orgánulo. METODOLOGÍA: Estudio del remodelado cardíaco en CIR en dos grupos de estudio: 1) fetos CIR humanos; 2) modelo animal de CIR previamente validado. Se han usado distintas técnicas avanzadas de imagen para estudiar el remodelado cardiaco en CIR: 1) micro-CT por rayos X generados por sincrotrón para el estudio de la arquitectura detallada del corazón; 2) microscopía electrónica de transmisión para la evaluación de la organización intracelular del cardiomiocito; 3) microscopia multifotón e imagen de segundo harmónico para el estudio de la morfometría del sarcómero. Se ha evaluado la función cardiaca mediante ecocardiografia y análisis bioinformático del perfil de expresión génica. RESULTADOS: A nivel de órgano, la orientación de las fibras se encuentra alterada en fetos CIR y los vasos coronarios dilatados. A nivel del cardiomicito, la organización intracelular presenta cambios afectando mayormente la relación entre mitocondrias y miofilamentos. La longitud del sarcómero, unidad contráctil fundamental, es inferior en corazones de fetos CIR. Esta última alteración persiste en vida postnatal. Los cambios estructurales de los corazones CIR se acompañan de signos de disfunción cardiaca subclínica y cambios en la expresión de grupos de genes funcionalmente relacionados, involucrados en la homeostasis del oxígeno, la producción de energía y la banda M del sarcómero. CONCLUSIONES: Los cambios descritos proporcionan evidencias de los mecanismos involucrados en el remodelado cardíaco asociado al CIR. Además, dichos cambios estructurales se asocian con una disfunción cardíaca y cambios a nivel de expresión génica.

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[eng]INTRODUCTION: Intrauterine growth restriction (IUGR) due to placental insufficiency affects up to 7-10% of pregnancies and is a major cause of perinatal mortality and long term morbidity. IUGR results in low birth weight, which is associated with increased risk of cardiovascular mortality in adulthood, and is thought to be mediated by fetal cardiovascular programming. IUGR fetuses show signs of cardiac systolic and diastolic dysfunction from early stages, together with the appearance of biochemical signs of cell damage, changes in cardiac morphometry and function. These fetal changes persist permanently, resulting in vascular and cardiac remodelling. HYPOTHESIS: IUGR induces cardiac remodeling and dysfunction at organ, cellular and organelle level. OBJECTIVE: To characterize cardiac remodeling and function in IUGR, at organ, cellular and organelle level. METHODOLOGY: Cardiac remodeling due to IUGR has been evaluated in in two study groups: 1) human IUGR fetuses; 2) an experimental model of IUGR in New Zealand rabbit which has been previously validated. Several imaging techniques have been used to evaluate cardiac remodeling in IUGR: 1) X-ray synchrotron radiation to evaluate detailed cardiac anatomy; 2) transmission electron microscopy to study the intracellular organization of the cardiomyocyte; 3) multiphoton and second harmonic generation microscopy to evalaute the morphometry and ultrastructure of the sarcomere. Additionally, stuctural changes have been accompained with the evaluation of cardiac function with echocardiography and the evaluation of the gene expression profile. Cardiac remodeling has been evaluated in fetuses and the postnatal persistence of some of the changes has been assessed. RESULTS: At the organ level, fiber orientation is altered in IUGR fetal hearts and coronary vessels appear to be dilated. The intracellular organization of the cardiomyocyte of IUGR fetal hearts presents changes affecting the relationship between mitochondria and myofilaments. At the level of the sarcomere, which is the main contractile unit, sarcomere length results to be shorter in IUGR fetal hearts. The latest persists in postnatal life. Signs of cardiac remodeling of IUGR hearts are associated to a subclinical cardiac dysfunction and changes in the expression of groups of genes functionally related, involved in oxygen homeostasis, energy production and the M-band of the sarcomere. CONCLUSIONS: Signs of cardiac remodeling induced by IUGR are described in this Thesis, from the whole cardiac architecture, through the cardiomyocyte intracellular organization, to the ultrastructure of the sarcomere. Moreover, the structural changes are associated with cardiac dysfunction and gene expression alterations. Specifically, we demonstrate: 1) the detailed cardiac anatomy is different in IUGR fetal hearts, with changes in fiber orientation and coronary vessels dilation; 2) the arrangement of the intracellular organelles of the cardiomyoycte is altered in IUGR fetuses, affecting mitochondria and their interaction with myofilaments; 3) sarcomere length is shorter in IUGR fetuses, which could result in decreased contractility; 4) shorter sarcomere length persists in postnatal life, suggesting that IUGR-induced changes on sarcomere morphometry during fetal life could contribute to the increased risk of cardiovascular disease in adulthood; 5) the described changes of cardiac remodeling are associated with subclinical cardiac dysfunction in IUGR fetuses and changes in the expression of groups of genes involved in oxygen homeostasis, energy production and the sarcomere M¬band.

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Multiscale characterization of cardiac remodeling induced by intrauterine growth restriction, at organ, cellular and subcellular level