SYRCLE_Drongelen mini symposium sr animal studies 30082012
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Transcript of SYRCLE_Drongelen mini symposium sr animal studies 30082012
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Functional adaptation during pregnancy: a meta-analysis
of animal studies
J. van Drongelen
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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
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During pregnancy
Chamberlain and Broughton (1998); Slangen et al. (1996); Danielson et al. (1995)
Human Weeks of gestation
Rat Days of gestation NP 5 11 16 21
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Vasodilation
Mesenteric vascular bed important!
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Local vascular tone
EC
M
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Local vascular tone
EC
M
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Local vascular tone
Pressure
EC
M
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Local vascular tone
EC
M
Pressure
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Measuring vasomotion
SMC
Resp
on
se
EC
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Measuring vasomotion
EC50%
Emax
Effect
Stimulus
50%
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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
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Goal
Selection of studies concerning
• Healthy subjects in their first pregnancy
• Healthy nulliparous subjects
• Comparable age
• Vasodilator and vasoconstrictor mesenteric responses
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Pubmed and Embase search
Three components
1. Pregnancy
2. Mesenteric arteries
3. Vasodilator and vasoconstrictor responses
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Component Description
Pregnancy "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
vasodilator responses
"vasoconstriction"[MeSH Terms] OR "vasoconstriction"[tiab] OR
"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]
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Identified studies (n=398)
Subtracted studies (n=96)
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)
Included studies (n=55)
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 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)
Responses (r=78)- Response <5 measurements (r=38)- Other blockade than NO, PGI2, endothelium (r=40)
Inclusion and exclusion
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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)
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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%
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Meta-analysis
x3
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Results
= =
=
EC
M
Pressure
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In summary
SDR WR Mice Guinea pigs
Vasodilation
- flow-mediated vasodilation
.
.
- compliance = . .
- vasodilator agents (EC) =
- vasodilator agents (SMC) . . .
Vasoconstriction
- myogenic reactivity
?
=
.
.
- vasoconstrictor agents (SMC) = =
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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
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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
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Take home message
Systematic review of animal studies
There is no excuse
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Acknowledgements
Dr. CR Hooijmans
Dr. RBM de Vries
Drs. L. ten Bos
Prof. Dr. PABM Smits
Prof. Dr. FK Lotgering
Prof. Dr. MJ Ritskens
Prof. Dr. MEA Spaanderman