ACE inhibitors: protection against COVID-19?

There’s a crucial distinction between ACE2, the star of our show; and ACE, as in ACE inhibitors. They’re both in the same system, and both first and foremost seem to affect blood pressure, but in opposite ways. Let's look now at ACE. Hugh Montgomery is an intensive care specialist at University College London, and he explained to Phil Sansom what ACE does, what ACE inhibitors might do, and what role the genetics seems to play in all this…

Hugh - We all have two ACE genes and we can have one of two flavours. One's known as the I or insertion variant, which has got a tiny little extra chunk of DNA in it. And one's called the deletion or D variant, which has that little bit missing. That changes how much of this protein the gene makes. Which is called ACE.

Phil - So this isn't something that breaks the gene and stops it from doing stuff. This just changes what happens.

Hugh - That's right. Essentially it changes how much of this active protein you've got. And for a long time we thought the only reason this system existed was to control your blood pressure and for that very reason a bunch of drugs are made. These are called ACE inhibitors and they lower the amount of ACE activity and that lowers blood pressure. Now these drugs are widely used now, but it is true that this turns out not just to be something that regulates blood pressure, but it regulates the growth of cells and it also regulates their metabolism. You DDs in the audience, a bit like me, are likely to find that you can stack muscle on very easily with training. Whereas the II people, the low ACE activity people are very much better generally speaking at endurance. The I version of the gene is much more common in long distance runners. Now the D version is much more common in power lifters and rowers for instance.

Phil - What's the version that's really, really good at sitting down for long periods of time.

Hugh - Well do you know what there are even genes that influence whether you want to sit down on your rear end and watch Netflix all day!

Phil - I better thank Joe Wicks now for helping me overcome that stuff. Now when it comes to the coronavirus, this is sort of related, right? Because ACE acts as part of the same system as the thing that the virus attaches onto.

Hugh - Yeah, so this is really exciting. We were doing some work with mountaineers. These people climb of course very high and there the higher you go, the less oxygen there is. And we found that the I version of the gene was very, very much more common, much, much more common even than in marathon runners. Having those same genes massively influenced your chance of surviving from severe lung injury. In fact, you were five times less likely to die, which is way beyond any impact on mortality I could have as a competent and hardworking intensivist. So there are a couple of questions. The first of them is if we just took this coronavirus set of patients with very bad lungs and low oxygen, would they benefit from us giving them an ACE inhibitor and lowering ACE levels? Would we find a similar reduction in mortality? We don't know, but the data is suggesting that it might. If we look at the distribution of the I and D versions of the ACE gene around the world, the places that have much more I versions of the gene do seem to have less severe disease with coronavirus. And secondly, there's a three fold reduction in mortality in people taking an ACE inhibitor or actually something that blocks the product base, this angiotensin 2. Now that's not enough to prove the effect, but these data fit together to suggest that low ACE activity might work and we think this may give us a potential treatment that works. In fact, we're just about to start those trials hopefully soon with using those very same cheap, effective drugs that treat blood pressure and heart failure. If there were no such trial and there were no other options, my money were I betting, would be that the ACE inhibitor would work, but we're going to find out.

Phil - This is all such a far cry for when people were worried that these drugs would make the condition worse.

Hugh - Yes, and of course that was the first story. So when we first heard that ACE2 was the protein receptor for the spike protein of the coronavirus, we were all a bit anxious - should we be stopping ACE inhibitors on all the patients? And as it turned out, we don't see any signal for harm at all. So if I was an ACE inhibitor now listening to this podcast, I would continue to take it.