Dissertation committee:
Σουλτάνα Σιαχανίδου, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Χρούσος, Ομότιμος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Χριστίνα Κανακά-Gantenbein, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ευαγγελία Χαρμανδάρη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Φλώρα Μπακοπούλου, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Εμμανουήλ Ζουμάκης, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ελένη Παπανικολάου, Λέκτορας, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Introduction: Approximately, 11% of live born neonates, worldwide, has been born prematurely (<37 weeks of gestational age). Mounting evidence supports the adverse effect of prematurity on cardiovascular health; however, the underlying mechanisms connecting prematurity with the later onset of cardiovascular disease or explaining the association between preterm birth and endothelial dysfunction in later life are not fully understood. Endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) act as reliable, early biomarkers of endothelial damage. Circulating EMPs are described as small membrane vesicles, released from endothelial cells in response to stimuli such as inflammatory activation, apoptosis or injury. Circulating EPCs are bone marrow derived cells that proliferate and differentiate into mature endothelial cells, and they have critical roles in neovascularization and vascular repair. To the best of our knowledge, no studies have investigated circulating EMPs and EPCs in prepubertal children born prematurely.
Aim: The aim of this study is to evaluate circulating EMPs and EPCs levels in prepubertal children born prematurely, and to assess possible associations of EMPs and EPCs with cardiovascular risk factors and endothelial function parameters in our study population.
Materials and Methods: This cross-sectional study enrolled 136 prepubertal children; 63 preterm and 73 born at term, as controls. Circulating CD62E(+), CD144(+) and CD31(+)/CD42b(-) EMPs, as well as circulating CD34(+)/VEGFR-2(+)/CD45(-) and CD34(+)/VEGFR-2(+)/CD45dim EPCs were measured by flow cytometry in preterm-born children compared to controls. Anthropometric measurements, such as body mass index (BMI), waist-to-hip ratio (WHR) and neck circumference, systolic (SBP) and diastolic (DBP) blood pressure, hematological and biochemical parameters including complete blood count, glucose, insulin, HOMA-IR and lipid profile, as well as hemostatic/fibrinolytic parameters, such as fibrinogen, vWFAg, factors VIII and IX, proteins C and S, plasminogen and PAI-1, were evaluated. The platelet function was also evaluated by measuring the closure time using the collagen/epinephrine cartridge assessed by the platelet function analyzer 100 (PFA-100). In addition, common carotid (cIMT) and abdominal aortic (aIMT) intima-media thickness, endothelium-dependent flow-mediated dilation (FMD) of the brachial artery, and echocardiographic parameters, were assessed.
Results: Circulating CD62E(+), CD144(+) and CD31(+)/CD42b(-) EMPs, as well as circulating CD34(+)/VEGFR-2(+)/CD45(-) and CD34(+)/VEGFR-2(+)/CD45dim EPCs were significantly higher in preterm-born children compared to controls (p=0.01, p<0.001, p<0.001, p<0.001 and p<0.001, respectively). Maternal preeclampsia was associated with increased CD62E(+) and CD144(+) EMPs in the total study population, as well as with increased CD144(+) EMPs in the preterm-born group. Maternal gestational diabetes was associated with significantly decreased CD34(+)/VEGFR-2(+)/CD45(-) and CD34(+)/VEGFR-2(+)/CD45dim EPCs in the total study population, as well as in the preterm-born group. Moreover, prematurity was associated with higher waist circumference, higher WHR and neck circumference, higher SBP and DBP, higher uric acid levels, lower levels of protein S, higher PAI-1 levels, and prolonged closure time using the collagen/epinephrine cartridge assessed by the PFA-100. Prepubertal children born prematurely had also higher cIMT and aIMT, lower peak velocity of the brachial artery, as well as higher mean pressure and velocity of pulmonary artery compared to controls. Circulating EMPs and EPCs correlated independently with cardiovascular risk factors and hemostatic/fibrinolytic parameters in the total study population, as well as in the preterm-born group. Preterm birth was recognized as an independent predictor of each EMP and EPC subpopulation studied.
Conclusion: Circulating CD62E(+), CD144(+) and CD31(+)/CD42b(-) endothelial microparticles EMPs, as well as circulating CD34(+)/VEGFR-2(+)/CD45(-) and CD34(+)/VEGFR-2(+)/CD45dim endothelial progenitor cells (EPCs), are increased in prepubertal preterm-born children in comparison with peers born full-term, suggesting a possible correlation between prematurity and endothelial dysfunction. Maternal preeclampsia is associated with an increase in EMPs, while maternal gestational diabetes is associated with a decrease in EPCs. Whether EMPs and EPCs could act, in clinical practice, as a complementary tool for non-invasive evaluation of endothelium in preterm-born children, as well as for early detection of high-risk preterm-born individuals require further investigation.
