opinions on new _Nature_ article?

[expert@preeclampsia.org]

The article on angiotensinogen is being covered broadly in the popular press as "scientists discover cause of preeclampsia" with cure to follow shortly.

Could I get some Expert commentary on the significance of this finding? (We have a preliminary discussion going here -- I'm happy to be corrected if I've got this wrong.)

Thanks, Caryn

[expert@preeclampsia.org]

The actual role of angiotensin in preeclampsia in the pathophysiology has gone around in circles for years. Also this write up is atrocious and reminds me of the recent marketing of the press of the metabalomics The circumspect me is always annoyed by these approaches which unfortunately get much of the reading public hyped up.

At any rate at most this would be one cause of vasoconstriction and far from the cause of preeclampsia. Also recall all the antioxident preventative trials are yet to blossom and thus the word cure is premature.

ACEinhibitors are worse then D but not exactly X.

[expert@preeclampsia.org]

Here is my take on the paper:

I found the paper quite interesting. The authors have identified that angiotensinogen cleavage by renin is redox dependent and argue that oxidative stress may be responsible for angiotensin I release (locally at sites of oxidative damage), that may have detrimental consequences (for example in the placenta, where renin is locally made). Presumably the locally generated angiotensin I would be converted to angiotensin II by ACE (in the lung) which would cause systemic HTN and other vascular injury.

The implications of these findings are not only for preeclampsia but also for essential hypertension where David Harrison and others have shown a pathogenic role for oxidative stress. The paper does not explain why systemic angiotensin II and its downstream target like aldosterone are suppressed (not elevated as predicted) in preeclampsia (work done by Phyllis August) and have not shown that these angiotensinogen modifications are altered prior to clinical preeclampsia but these can form the basis of future work. The paper is quite impressive!!

With regards to message for patients these findings are very interesting and may form the basis for a therapeutic in the future, but still more works needs to be done. Thanks

[expert@preeclampsia.org]

I just received the article from my department and for those that do not have it it is attached. Worse than I thought for all the brouhaha. One 24 PE and 12 controls but only 10 dots on fig 4 with lots of overlap. Ironically oxidative effects are also raised in contols but they have lower BP in pregnancy. The article referenced concerning treating a mouse model with an antioxident is a terrible model the kidneys show sclerosis etc not endotheliosis, However the gist of the research has general interest.

[expert@preeclampsia.org]

Agree with *****. Several times a year, a basic science paper is published that has some relevance to preeclampsia - but is hyped as "one step short of a cure." The logical step from this paper could be use of ACE-inhibitors with appropriate attention to fetal effects.

We have some published experience with intentional use of ACE-inhibitors in pregnancy. In conditions such as branch stenosis of the renal artery where activation of the renin-angiotensin axis is anticipated, they can make uncontrollable hypertension controllable. In advanced preeclampsia with resistant vasoconstriction, they do not seem to make much of a difference - too little too late.

Could use early in pregnancy, justified by the findings of this paper, improve outcomes? It seems plausible. A trial to assess the potential would need to be conducted in a very rigorous environment of fetal surveillance. That said, the paper describes a potential pathway of pathophysiology in preeclampsia. If we have learned anything from trials in the past, the pathways of pathophysiology are probably redundant. The potential positive impact would probably be incremental - not absolute.

There is data from the diabetes literature that use of ACE-inhibitors 6 months prior to pregnancy, (stopped when conception occurs), can dramatically reduce the expression of proteinuria in pregnancy. One can certainly debate whether this impact is relevant to clinical outcomes in pregnancy. Sibai's paper from the high risk ASA study suggested that htn and proteinuria early in pregnancy predicted adverse neonatal outcome.

[expert@preeclampsia.org]

I agree with *****. This is an interesting finding and perhaps has eventual implications perhaps even therapeutic for preeclampsia but very far from "ready for prime time"

[expert@preeclampsia.org]

It is unfortunate that investigators are now using the lay media to promote their interests. We have been through so many of these publications suggesting predction, cause of disease and possible treatment. The bad thing is that the most vulnerable patients are the most affected with these reports, giving them some times false hopes and unrealistic expectations.

May be, we need to have a discussion with those on line medical services about their responsibility when it comes to such reporting. Maybe I am naive?

[expert@preeclampsia.org]

I think it is important to distinguish between physiologic stimulation of the renin angiotensin system, and excess, inappropriately suppressed angiotensin II; As we and many others have shown, normal pregnancy is characterized by vasodilation, and physiologic stimulation of the RAS - renin and Ang II are higher, and the more vasodilation the greater the rise in renin; I have also viewed the lower renin/aldo and AII levels in PE as an expected response to vasoconstriction and decreased sodium excretion; could there be 'not enough' suppression of the RAS in PE? Possibly.

Anyway, I agree with ***** and others that this was a ridiculous claim on the part of the editorial.

[expert@preeclampsia.org]

Also, an index case of a mutation resulting in increased angiotensinogen cleavage in a woman with preeclampsia is cited; we looked for this mutation in a small sample (32) of cases and couldn't find it in any cases; Hypertens. 2000 Feb;18(2):173-8; Our negative finding was not cited in this paper.