syrcle_drongelen mini symposium sr animal studies 30082012

Functional adaptation during pregnancy: a meta-analysis

of animal studies

J. van Drongelen

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

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

Vasodilation

Mesenteric vascular bed important!

Local vascular tone

EC

M

Local vascular tone

EC

M

Local vascular tone

Pressure

EC

M

Local vascular tone

EC

M

Pressure

Measuring vasomotion

SMC

Resp

on

se

EC

Measuring vasomotion

EC50%

Emax

Effect

Stimulus

50%

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

Goal

Selection of studies concerning

• Healthy subjects in their first pregnancy

• Healthy nulliparous subjects

• Comparable age

• Vasodilator and vasoconstrictor mesenteric responses

Pubmed and Embase search

Three components

1. Pregnancy

2. Mesenteric arteries

3. Vasodilator and vasoconstrictor responses

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]

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

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)

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%

Meta-analysis

x3

Results

= =

=

EC

M

Pressure

In summary

SDR WR Mice Guinea pigs

Vasodilation

- flow-mediated vasodilation

.

.

- compliance = . .

- vasodilator agents (EC) =

- vasodilator agents (SMC) . . .

Vasoconstriction

- myogenic reactivity

?

=

.

.

- vasoconstrictor agents (SMC) = =

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

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

Take home message

Systematic review of animal studies

There is no excuse

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