Family doc here. I've been reading a lot and it is currently thought that the coronavirus requires an ACE 2 receptor for cell entry. I've seen a few prelim articles with mixed thoughts, but would an ARB help prevent cell entry by the virus?

Maybe should have posted on the nerdery?

Try asking the question directly to the couple of docs posting in the OP pinned up top?

Nothing to offer but appreciation for the effort.

Two lines of thought here, good and bad. (I'm not a doc but take ACE-I's and have concern. )

I did find it strange that I think currently the highest correlated comorbidity with the fatalities is hypertension. I mean, is it the hypertension, or is it the people utilising medicines that proliferate the catalyst for virus reproduction.....

https://www.thesun.co.uk/news/11168074/medicine-millions-increase-coronavirus/amp/

https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang

I am curious also. Seems like an ARB could compete at receptor sites against this virus if indeed it gains cell entry via ACE2.

Of course Not Yet Dr, but it'd be foolish to eliminate medicines which cause an upregulation of ACE2 as a consideration....

McInnis 03 said:

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Of course Not Yet Dr, but it'd be foolish to eliminate medicines which cause an upregulation of ACE2 as a non consideration....

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It would be even more foolish to stop taking medications based on unsubstantiated fears. Currently there is no evidence to suggest anyone is at increased risk by taking an ACE-I.

Medical evidence often takes years, so of course the proof can't be there but the commentary is valid and could be worth discussing with your doctor.

https://www.google.com/url?sa=t&source=web&rct=j&url=https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30116-8.pdf&ved=2ahUKEwjd7t27vZvoAhVJ-6wKHQCzCzoQFjAAegQIAhAB&usg=AOvVaw1X0DXfLj5hXKnWjwxKC0xl

McInnis 03 said:

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Medical evidence often takes years, so of course the proof can't be there but the commentary is valid and could be worth discussing with your doctor.

https://www.google.com/url?sa=t&source=web&rct=j&url=https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30116-8.pdf&ved=2ahUKEwjd7t27vZvoAhVJ-6wKHQCzCzoQFjAAegQIAhAB&usg=AOvVaw1X0DXfLj5hXKnWjwxKC0xl

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Yes, but trends can often be picked up quickly. Important to note that your link is to a correspondence to Lancet that is not peer reviewed and should not be held to any standard higher than an individual's opinion.

When people throw out numbers like 23.7% of patients in a study with severe disease had hypertension, it is important to know what the baseline prevalence of this specific co-morbidity is. Is 23.7% significantly different from the population of concern's baseline prevalence? We don't know. However, it would appear that in China, 23.2% of the population over the age of 18 have a history of hypertension based on an article from Circulation from 2018. That appears to be quite similar to the prevalence of hypertension in those with severe disease in one of the studies cited in the correspondence. This would imply that if ACE-Is actually do negatively effect those infected with COVID-19, it is of minimal significance.

I have not spent much time studying this pathway, but this is a link to a summary from an online journal club.

http://www.nephjc.com/news/covidace2#

Several studies linked as part of discussion. One that stood out to me was regarding potential mechanism of ARB.



The discussion suggests that perhaps CoV would not be able to bound ACE2 if AT1R-ACE2 is stabilized, but I don't think that's a great assumption without reason to thing that the surface CoV binds to is blocked. Just because two surface proteins are interacting would t necessitate, at least in my kind, that another protein could not bind one of them. No info suggesting direct competition.

That said, the mechanism described seems to open up how CoV might enter. If AngII disrupts the complex at high concentration, then ACE2 enters the cell for lysosomal destruction, potentially dragging along a bound virus?

It would seem to me if this is correct, that ARB might help to deny CoV access to the cell via suppression of ACE2 destruction. It looks like there are reports that University of Minnesota is trying to start a Losartan trial (not in clinicaltrials.gov yet)
http://m.startribune.com/university-of-minnesota-to-test-three-drugs-for-covid-patients/568766632/

Regarding ACE inhibitors, maybe similar upstream effect by blocking AngI ->AngII?

As for the risk of ACE2 increased expression, the same journal club article discusses this being observed in rodent models, but not confirmed in humans. Seems like People aren't happy about suggestion that these therapies are a risk for infection.

https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang

So do we need to quit our lisinopril (20mg once a day)? I also take toprol and that can probably keep my bp low enough by itself.

00AGof3 said:

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So do we need to quit our lisinopril (20mg once a day)? I also take toprol and that can probably keep my bp low enough by itself.

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Likely won't be recommended but you can talk to your doctor.

Absolutely not.

First, progressive cardiovascular disease is apparently a much larger direct risk to you than coronavirus infection. Like astronomically larger.

Second, it would appear that several cardiologists are trying to advise against this action as it may be a very dangerous panic response rooted in little to no scientific basis.

Finally, if the mechanism above is to be believed (which you as a lay person [assumed] and patient under medical treatment should not do at this time), your ACE inhibitor may be suppressing a downstream action that could increase your risk of infection.

Listen to your doctor. Take your meds.

Thanks guys.

Nice points and great discussion, thanks so much!

Good stuff.

Well, this is all worrisome. I take lisinopril 10 mg. I appreciate all the discussion.

Why worrisome?

The mere fact that it has occurred to someone that there may be a connection between ACE inhibitors and the virus scares me. I very much appreciate all the resources and comments here. I guess I should be reassured.

And some more...

As is usually the case, despite what my grade school teacher friends like to tell people, Wikipedia is a treasure trove of information once you follow references...

https://www.nature.com/articles/nm1267

Again, rodent models. But it appears that a well-cited article from 2005 described a good deal of mechanism related to SARS spike protein, lung injury, and renin-angiotensin system. Of note:
- ACE2 is the major binding point for SARS spike protein. (This is well staged in all media today.)
- Binding of the spike protein to ACE2 significantly down-regulates ACE2 expression.
- Binding of the spike protein to ACE2 in models of acute lung injury significantly worsened lung injury, but not in ACE2 KO mice (ie, the worsening was specific to spike protein-ACE2 binding)...but wait for it...

- the Spike protein induced lung injury, as well as pulmonary edema, were attenuated with treatment of AT1R inhibitor (Losartan at 15mg/kg [probably not a good human dose])

So, Infection happens by binding to ACE2, the reduces ACE2 expression, thereby destabilizing renin-angiotensin system and making lung injury more severe.

If true, something that might increase ACE2 expression might have some protective effect with respect to severity of lung injury, a major part of what is reported to be killing people.




Now for some blind speculation....

Many of the experiments in that paper were conducted with a recombinant spike protein to make sure that this binding was the source of what was studied. Therefore, destabilization of renin-angiotensin was caused only by the binding to the surface receptor (not some other action by the virus).

Several of the vaccine development projects I've read about are based on the spike protein. In fact, Moderna's mRNA vaccine, as I understand it, is intended to deliver mRNA to encode the CoV spike protein for the host cell to reproduce and then make antibodies against.

If the spike protein itself can cause so much damage, what's the chance that vaccines that present spike protein as the antigen might cause lung injury themselves. Hopefully muted if the vaccine is not inhaled, but ***** Hopefully also muted by giving as a finite dose that doesn't also replicate itself.

**** like this is why they need to be tested in safety trials and not distributed in mass as soon as a lab says they have one.

OldArmy71 said:

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The mere fact that it has occurred to someone that there may be a connection between ACE inhibitors and the virus scares me. I very much appreciate all the resources and comments here. I guess I should be reassured.

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Yeah don't read too much into it. The virus uses receptors in this pathway as an entry point, so there's almost certainly some connection worth exploring. The systems are very complex though, with dozens of compensatory mechanisms, so you can't overreact from connection alone.

Heart disease is still more likely to kill you.

This is great stuff and thank you! I'll be curious once we have more testing to see if patients that are on an ARB are less likely to be infected. Sounds plausible at least!

And you are right, that level of losartan is not a good human dose!

HillcountryAg97 said:

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And you are right, that level of losartan is not a good human dose!

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Yeah, in vitro assays. Proves there's legs to the interaction. Doesn't prove that it matters in practice.

At the very least it would seem by that study that ARBs may have a beneficial result, thereby limiting the rationale that someone taking it for a medically appropriate purpose should stop.

I've seen this cited as why vaccine development might not be easy. Is this related:

https://www.tandfonline.com/doi/full/10.1080/21645515.2016.1177688

Maybe, but not certain. That publication is for MERS virus, related coronavirus. Also references a similar study in the SARS-CoV virus. Both had similar results.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335060/?report=reader#!po=0.781250

Apparently, they report being able to create successful vaccines with multiple strategies, but that it creates a hypersensitive immune response upon challenge with the infection.

basically, the experiment goes like this:
- animals are given a vaccine and are shown to produce antibodies against the virus
- animals are purposely infected with the virus and shown to be resistant to viral infection.
- animals that resisted infection are shown to have developed a severe lung pathology in response to immunoreaction.

In short, the vaccine worked but, the animals were in worse shape once they got infected later. This happens in multiple organism models. In the SARS paper, one of the conclusions was to advise against proceeding with human trials.

That's kind of alarming because it would suggest that short term safety trials might look good in humans, only to find out that getting the virus will hurt you real bad, specifically because you were immunized. Apparently this has happened with RSV and killed infants previously, which is why there isn't a vaccine for RSV.

Thanks for the insight. There was some speculation about a month ago that perhaps the bad results in Wuhan were due to previous vaccine testing or vaccine deployment over-sensitizing that population. Italy seems to have shown that was wishful thinking.

As an aside, there was mention on CNBC about two weeks ago that at a White House Pharma Summit one of the company CEOs cautioned everyone that sometimes trialed vaccines leave recipients worse off.

https://peterattiamd.com/covid-19-update-03152020/

podcast/show notes From Peter Attias "The Drive" regarding this topic.