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SYRCLE_Drongelen mini symposium sr animal studies 30082012

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  • 1. Functional adaptation during pregnancy: a meta-analysis of animal studiesJ. van Drongelen
  • 2. Insight in: 1. Cellular pathways involved in pregnancy-induced vasodilation 2. Systematic overview of literature (mesenteric arteries) 3. Advantages of systematic review of animal studies
  • 3. During pregnancyHuman Weeks of gestationRat NP 5 11 16 21 Days of gestation Chamberlain and Broughton (1998); Slangen et al. (1996); Danielson et al. (1995)
  • 4. Vasodilation Mesenteric vascular bed important!
  • 5. Local vascular tone ECM
  • 6. Local vascular tone ECM
  • 7. Local vascular tone ECM Pressure
  • 8. Local vascular tone ECM Pressure
  • 9. Measuring vasomotion ResponseSMC EC
  • 10. Measuring vasomotion Effect Emax 50% Stimulus EC50%
  • 11. Summary • Pregnancy induces vasodilation • Two types of stimuli (pharmacological / mechanical) • G-protein coupled receptors are important • Theories mainly based on rats  Mesenteric system is important  Conflicting results in literature Idea • Systematic review  Effect of first pregnancy on vascular responses in mesenteric arteries
  • 12. Goal Selection of studies concerning • Healthy subjects in their first pregnancy • Healthy nulliparous subjects • Comparable age • Vasodilator and vasoconstrictor mesenteric responses
  • 13. Pubmed and Embase search Three components 1. Pregnancy 2. Mesenteric arteries 3. Vasodilator and vasoconstrictor responses
  • 14. Component DescriptionPregnancy "pregnancy"[MeSH Terms] OR "pregnancy"[tiab] OR "pregnancies"[tiab] OR "gestation"[tiab] OR "pregnant"[tiab] OR "maternal-fetal relations"[tiab]Mesenteric arteries "mesenteric arteries"[MeSH Terms] OR "Mesentery/blood supply"[Mesh] OR "mesenteric"[tiab] OR "mesentery artery"[tiab] OR "mesentery arteries"[tiab] OR "mesenterial artery"[tiab] OR "mesenterial arteries"[tiab] OR "arteria mesenterica"[tiab] OR "omental microvessels"[tiab] OR "omental arteries"[tiab] OR "omental artery"[tiab]Vasoconstrictor and "vasoconstriction"[MeSH Terms] OR "vasoconstriction"[tiab] ORvasodilator responses "vasoconstrictions"[tiab] OR "vasoconstrictor agents"[MeSH Terms] OR "vasoconstrictor agents"[Pharmacological Action] OR "vascular resistance"[MeSH Terms] OR "vascular resistance"[tiab] OR "vascular capacitance"[MeSH Terms] OR ("vascular"[tiab] AND "capacitance"[tiab]) OR "vasoconstrictor"[tiab] OR "vasoconstrictors"[tiab] OR "vasopressor"[tiab] OR "vasoactive agonist"[tiab] OR "vasoactive agonists"[tiab] OR "vasopressors"[tiab] OR "vasomotor system"[MeSH Terms] OR "vasomotor system"[tiab] OR "peripheral resistance"[tiab] OR "artery constriction"[tiab] OR "vessel constriction"[tiab] OR "vasoconstrictive"[tiab] OR "vasoconstricting"[tiab] OR "vasoconstricted"[tiab] OR "vasodilation"[MeSH Terms] OR "vasodilation"[tiab] OR "vasodilatation"[tiab] OR "vasodilatating"[tiab] OR "vasodilating"[tiab] OR "vasodilative"[tiab] OR "vasodilatative"[tiab] OR "artery dilation"[tiab] OR "vessel dilation"[tiab] OR "artery dilatation"[tiab] OR "vessel dilatation"[tiab] OR "vasodilator agents"[MeSH Terms] OR "vasodilator agents"[Pharmacological Action] OR "vasodilator"[tiab] OR "vasodilators"[tiab] OR "vasorelaxation"[tiab] OR "Vascular Endothelium Dependent Relaxation"[tiab] OR "Endothelium Dependent Relaxation"[tiab] OR "Vascular Endothelium-Dependent Relaxation"[tiab] OR "Endothelium-Dependent-Relaxation"[tiab] OR "hemodynamics"[MeSH Terms] OR "hemodynamics"[tiab]OR "hemodynamic"[tiab] OR "vasodilated"[tiab] OR "vasoactive agent"[tiab] OR "vasoactive drug"[tiab] OR "vasoactive drugs"[tiab] OR "dilation"[tiab] OR "dilatation"[tiab] OR "contraction"[tiab] OR "relaxation"[tiab]
  • 15. Inclusion and exclusion Identified studies (n=398) Title and abstract (n=302) - No healthy first pregnancy versus virgin control (n=258) - No mesenteric artery vasoconstrictor/vasodilator response (n=19) - No standard medium (n=5) - No original data; review (n=20) Subtracted studies (n=96) Full article (n=43) - No healthy first pregnancy versus virgin control (n=12) - No mesenteric artery vasoconstrictor/vasodilator response (n=26) - No age-matching (n=5) Included studies (n=55) Responses (r=78) - Response <5 measurements (r=38) - Other blockade than NO, PGI2, endothelium (r=40) Included responses (r=188) - Pharmacological / Electrical (r=160) * EC50 described (r=83) * Emax described (r=63) * Graph present (r=130) - Mechanical (r=28) * Graph present (r=27)
  • 16. Study characteristics Species (55 studies) • Rodents: - rat (n=46)  SDR (n=27)  WR (n=15)  unknown (n=1) - mouse (n=5) - guinea pig (n=2) • Rabbit (n=1) • Pigs (n=1) Gestational period (188 responses) • Early (r=3) • Mid (r=23) • Late (r=161) • Unknown (r=1)
  • 17. Quality Randomization 4% Blinding 0% Pharmacological stimuli • EC50% 52% • Emax 39% • Graph 81% • Clear number 74% Mechanical stimuli • Effect size 7% • Graph 96% • Clear number 92%
  • 18. Meta-analysis x3
  • 19. Results    = = =  ECM Pressure 
  • 20. In summary SDR WR Mice Guinea pigsVasodilation- flow-mediated vasodilation   . .- compliance  = . .- vasodilator agents (EC)  =  - vasodilator agents (SMC)  . . .Vasoconstriction- myogenic reactivity ? = . .- vasoconstrictor agents (SMC)  =  =
  • 21. Conclusion 1. Most studies concern late pregnancy 2. Quality is limited 3. Flow-mediated vasodilation is uniformly upregulated 4. Heterogeneity amongst species 5. Importance of systematic reviews for animal data 6. Difficulty in extrapolation to vasodilator pathways involved in human pregnancy
  • 22. Take home message Systematic reviews of animal studies • Give new insight • Identify lacunas in knowledge • Lead to new original research • Increase efficancy of animal use • Reduce unnecessary use of animals
  • 23. Take home message Systematic review of animal studies There is no excuse
  • 24. Acknowledgements Dr. CR Hooijmans Dr. RBM de Vries Drs. L. ten Bos Prof. Dr. PABM Smits Prof. Dr. FK Lotgering Prof. Dr. MJ RitskensProf. Dr. MEA Spaanderman