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Is this the pathophysiology of preeclampsia?

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Expand view Topic review: Is this the pathophysiology of preeclampsia?

Re: Is this the pathophysiology of preeclampsia?

Post by caryn » Sat Jan 07, 2012 10:42 am

? But this is just a consequence of how placentas develop: the trophoblast burrow into the maternal spiral arteries during initial implantation. Their normal development is known to be compromised in preeclampsia; PE placentas on biopsy have developed with inadequate remodeling.

http://atvb.ahajournals.org/content/25/1/102.full.pdf is one discussion but there are hundreds if you search strings like "trophoblast spiral artery first trimester". It starts Remodeling of the uterine arteries is a key event in early pregnancy. In the first trimester of pregnancy, a subpopulation of fetal trophoblast cells, the extravillous trophoblast, invade the uterine wall (interstitial invasion) and its blood vessels (endovascular invasion) as far as the myometrial segments. In the uterine spiral arteries, the trophoblasts interdigitate between the endothelial cells (ECs), replacing the endothelial lining and most of the musculoelastic tissue in the vessel walls. This creates a high-flow, low-resistance circulation that increases maternal blood flow to the placental villi at the maternal–fetal interface... Defective remodeling of the spiral arteries is associated with pregnancies complicated by preeclampsia and intrauterine growth restriction (IUGR) and is proposed to lead to an overall state of oxidative stress or fluctuations in oxygen concentrations analogous to hypoxia-reperfusion within the placental environment...

Is that what I wasn't explaining?

ETA: also useful: a Google Image search of "spiral artery remodeling preeclampsia"

ETA: also useful: http://dmm.biologists.org/content/5/1/9.long

It is clear from placental samples examined at term, as well as from Doppler ultrasound study of placental perfusion, that the remodeling of spiral arteries is incomplete in patients with preeclampsia. Fewer trophoblast cells are present within the spiral arterioles, and the vessel walls remain stiff (Khong et al., 1986; Aquilina and Harrington, 1996). Although, by definition, preeclampsia can be diagnosed only after the 20th week of pregnancy (and clinically typically presents even later), this vascular remodeling occurs during the first two trimesters. In normal pregnancies, endovascular extravillous cytotrophoblast cells have been identified by 9 weeks of gestation (Craven et al., 1998), and intervillous blood flow is not established until 10–12 weeks of gestation (Caniggia et al., 2000; Burton et al., 2009). Thus, poor trophoblast invasion is an early event in disease progression, although it has not been determined whether it is the cause of preeclampsia or a result of another underlying problem.

Re: Is this the pathophysiology of preeclampsia?

Post by rodin » Fri Jan 06, 2012 06:49 am

I feel we are repeating ourself.You write: it happens right at the beginning during initial implantation.
I still have not seen the evidence to prove it happens right at the beginning during initial implantation.

I'm NOT suggesting randomizing women to sleep on their left side pre pregnancy. I don't see any logic in it.
I was just referring to the only recent study I'm aware of on left side sleeping. It is indeed on stillbirth and has nothing to do with preeclampsia.
Although the underlying pathophysiology could be similar.

Re: Is this the pathophysiology of preeclampsia?

Post by caryn » Fri Jan 06, 2012 08:36 am

Preeclampsia rates weren't higher in that study; it's a study of stillbirth...

Of course shallow implantation is secondary to apoptosis of placental cytotrophoblast, but that isn't secondary to compression of the renal vein by the larger pregnant uterus, because it happens right at the beginning during initial implantation. Are you suggesting randomizing women to sleep on their left side pre pregnancy, and if so, why? The weight of the uterus plus a blastocyst is negligibly different from the weight of the non pregnant uterus, right?

Re: Is this the pathophysiology of preeclampsia?

Post by rodin » Thu Dec 22, 2011 04:03 am

I'm not rejecting the studies that have found deranged and shallow placentation in preeclampsia patients. I'm suggesting that this shallow placentation is secondary to apoptosis of placental cytotrophoblasts.
The only recent study of left side sleeping I'm aware of is on the association between maternal sleep practices and risk of late stillbirth. http://www.ncbi.nlm.nih.gov/pubmed/21673002

Re: Is this the pathophysiology of preeclampsia?

Post by caryn » Thu Dec 22, 2011 10:58 am

If you're going to reject the (literally hundreds - the articles I linked are only the tip of the iceberg) of studies that have found deranged and shallow placentation in preeclampsia patients, then I suppose you'll need to find some current studies showing that modifying sleeping position affects preeclampsia rates in humans. This still would not explain why preeclamptic placentas initially develop so differently from the placentas from normal pregnancies, from the first trimester.

You might also be interested in the studies linked from my .sig file, which are work nailing down the production of soluble flt by the placenta as a consequence of shallow implantation and subsequent hypoxia.

The rollover test has been abandoned IIRC (notice the publication date of 1983) - because it *didn't* pan out in later work.

There are ways to compromise the endothelium that don't involve compression or kinking of the renal artery - like binding all the free VEGF. There is strong support in the research literature for an upregulation of soluble flt before arterial compromise, which is why the diagnostic tests in developments pick up preeeclampsia early in the third trimester before the onset of any maternal symptoms.

The women posting here would like nothing more than a therapy for preeclampsia.

Re: Is this the pathophysiology of preeclampsia?

Post by rodin » Thu Dec 22, 2011 08:01 am

Dear Caryn,
I have taken some time to read the articles you have referred to. In them I have found:
- Evidence that the invading placental trophoblast cells express HLA (Human Leukocyte Antigen) family known as HLA-C.
- Evidence that the maternal receptors that recognize and interact with HLA-C are the KIR family (Killer Immunoglobulin-like Receptors).
- Evidence that genetic differences and combinations in two gene families (HLA and KIR) are a risk factor for preeclampsia.
- Evidence that during early pregnancy, trophoblast cells, invade into the uterus and tap into the mother’s blood supply to sustain the growing baby.
- The hypothesis that initial or primary failure of the placenta to implant correctly into the uterus or womb causes insufficient blood supply to the unborn baby and could cause preeclampsia.
- The hypothesis that sometimes the combination of these genes (HLA and KIR) from mother and baby could result in inadequate invasion and lead to preeclampsia.

I would have to agree with you that when there is evidence of failure of the placenta to implant normally in very early stages of the pregnancy in PE, this would be an important argument against the renal vein compression hypothesis. (Or, at least it would mean renal compression is not involved in all “forms” of preeclampsia) However, I didn’t find this evidence.

An alternative is not impossible: The placenta keeps on growing during a normal pregnancy. When a normal developing placenta and unborn baby are confronted with vasoconstrictive spinal arteries and arteriole and are deprived of oxygen, this could lead to damage and cell death in the placenta. Because of be increased possibility for exudation the contact between placental trophoblast cells with maternal leukocytes could then take place. In the end this could account for the placental changes observed in preeclampsia.

I agree with you that new studies on left side sleeping have methodological difficulties. Double blind is impossible and randomization difficult. An option would be to take a large enough population of pregnant women and study the effect of advising left side sleeping on the incidence of preeclampsia. If this results in a clear drop in incidence this could become an treatment option.
There already have been studies in the past that had encouraging results in al small population of women at risk of preeclampsia. http://www.ncbi.nlm.nih.gov/pubmed/6846433

The renal compression hypothesis itself could be confirmed by studying the renal vein diameter, RAS reaction and blood pressure in reaction on different women body positions. But read the references of the article, a lot of evidence is already available. There is for instance a clear dilatation of the left renal vein in preeclampsia. (Just before it crosses between the aorta and the superior mesenteric artery.)
http://www.ncbi.nlm.nih.gov/pubmed/11243294
This would be difficult to explain without the renal vein compression hypthesis.
Stenting could become an option in women in which the renal vein blockage is clearly visualized.

Finally, as you state preeclampsia is very much a human disease. This is (in my opinion) because animals do not tend to sleep on their back.

Re: Is this the pathophysiology of preeclampsia?

Post by caryn » Sun Dec 18, 2011 05:20 am

I just remembered this article, which might make more sense than what I type in a hurry between Christmas parties! :D

http://www.preeclampsia.org/component/l ... ember-2010

"The invading placental trophoblast cells intermingle with maternal immune cells in the uterine lining. Trophoblast express not only maternal but also paternal genes and these will be different or “foreign” to the mother. Maternal immune cells can recognize these “foreign” fetal molecules and are thought to regulate the implantation process, allowing sufficient but not excessive invasion of the placenta. In the preeclamptic pregnancy this interactive process goes wrong and there is inadequate modification of the blood vessels which can lead to “starvation” of the placenta and subsequently triggering of the preeclamptic syndrome later in gestation in the mother..."

Re: Is this the pathophysiology of preeclampsia?

Post by caryn » Sun Dec 18, 2011 05:02 am

Nope; the primary immune conflict happens at implantation and compromises the depth of implantation of the placenta. KIR-AA/HLA-C conflicts happen at the initial stages of spiral artery remodeling by the trophoblast: http://www.ncbi.nlm.nih.gov/pubmed/21873457 and result in less broadening of the interface at the placental interchange: http://www.ncbi.nlm.nih.gov/pubmed/21743843 (pull the datasets.) http://www.nature.com/nri/journal/v2/n9 ... 86_F2.html is a picture of the inadequate depth of implantation of those trophoblast.

There is certainly *also* an inflammatory response following hypoxia, but that's not the initial problem! :D

With respect to compression of the renal artery - the obvious way to test this would be to randomize populations, and that's a problem, since women are going to know which side they're sleeping on and be able to use Google to find out that the conventional recommendation is to sleep on the left because it relieves the compression of the main artery supplying the placenta. That said, we could try stenting animal models - though animal models are *horrible* for preeclampsia research since it's a human disease. (No one would even entertain stenting human women, especially in the absence of a predictive test.) So if those options are out, that leaves looking to see if advising women to sleep on the left side or use bedrest is in anyway advantageous to prolonging delivery, and the data here are shoddy. I'd be interested to see a randomized controlled trial of bedrest vs. activity (again, this is unblindable.)

There are a *lot* of therapies compatible (in this broad sense) with the known immune reactions in preeclampsia, but without hard data... *shrug*

Re: Is this the pathophysiology of preeclampsia?

Post by rodin » Sun Dec 18, 2011 04:27 am

If I understand you correctly, you are saying that the maternal immune system contributes to the development of pre-eclampsia and that this can't be explained by a compression of the renal vein.
When we look at the mechanism
(Activated RAS --> vasoconstriction --> organ and placenta hypoxemia --> vascular damage --> symptoms)
the influence of the maternal immune system comes in at the stage of vascular damage.

For instance look at this article:
http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed
When you look at figure 1: you see how a cascade of inflammatory effects could follow the placental ischemia. This placental ischemia could be the result of vasoconstriction secondary to angiotensin II. Differences in the maternal immune system could in this way (because they influence the inflammatory response) be a risk factor for preeclampsia.

In this article
http://ajprenal.physiology.org/content/288/4/F614.long
the author states: Convincing evidence of the elevation of angiotensin II in preeclampsia does not exist despite the fact that much of vascular pathogenesis appears to be due to angiotensin type I (AT1) receptor activation. Vascular maladaptation with increased vasomotor tone, endothelial dysfunction, and increased sensitivity to angiotensin II and norepinephrine in manifest preeclampsia may be explained on the basis of angiotensin II-mediated mechanisms.
This hypothesis explains where this elevated angiotensin comes from.

I'm not suggesting everything is clarified now, but I'm saying that this hypothesis could be compatible with the known immune reactions in preeclampsia.

There's also the problem of women who are advised to sleep on their left sides and who get preeclampsia anyway. *raises hand*
Women would develop preeclampsia when there is a "long enough" compression of a renal vein. The anatomy of the women, her body position or maybe even the movement of the unborn baby might be of influence on the compressing a renal vein. There is no guaranty that even continues lying on the left side would protect against preeclampsia in all women.

Re: Is this the pathophysiology of preeclampsia?

Post by caryn » Sun Dec 18, 2011 03:28 am

Careful - just being different and new doesn't make it a better hypothesis! Any new proposal for pathophysiology has to take into account the known evidence about this condition, which includes several phenomena you wouldn't be able to account for with simple kinking of the renal vein, like this: http://www.ncbi.nlm.nih.gov/pubmed/1729 ... stractPlus

There's also the problem of women who are advised to sleep on their left sides and who get preeclampsia anyway. *raises hand*

None of that is to suggest that we're locked into a particular explanation here, any more than we'd run with Newton over Einstein. It's just to point out that an explanation of preeclampsia has to account for many different phenomena, and activation of the renin-angiotensin system is just one of those.

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