Cardiac Vascular Remodeling And Functional Interaction PDF Download

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.