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welcome to another med cram kovat 19
updates you can see the numbers here
they are starting to exceed that of
mainland China when we look globally
what I wanted to get to today is
something that a lot of you have
commented on and that is the receptor
for the SARS cough - virus that causes
kovat 19 and that is the ACE 2 receptor
the h2 receptor is how the virus gets
into the cell
it's the doorway and it's more than just
the doorway and today we're going to be
talking about exactly what the ACE 2
receptor is and what it's involved in
and why that matters
I've been wanted to do this for a long
time but the more I looked into it the
more complicated and interesting at the
same time that it was so I wanted to do
the research first and then tell you
where we are right now this has reached
a head because there are a number of
people out there that are actually
taking different sides on this issue of
the receptor so what it boils down to
basically as as we've talked before
outside of the cell or on the surface of
the cell there is a receptor for the
SARS cub to virus which is the thing
that causes kovin 19 which is the corona
virus and so here we have the virus and
it's got these projections that make it
look like rays of the Sun that's why
it's called the corona virus this is
SARS curve - this is 2019 corona virus
here is the s protein that we've talked
about and the receptor or this is on the
surface of the cell
specifically cells that are found in the
lung the type to nuuma site it's known
as and also in the GI tract and this
receptor is known as ace - and that's
really important for you to understand
ace - this is where the s protein docks
and then there's another protein called
a serine protease which is also here in
the membrane which helps to internalize
this virus into the cell and it allows
the
messenger RNA which is in here to come
in and infect the cell the key here
though is this protein that is on the
side of the cell is a stew and it's
exactly the same protein that was the
receptor for the SARS of virus that was
back in 2002 so the question is why is
this such a problem well there is some
animal data that's angiotensin receptor
blockers which is a very common type of
high blood pressure medication and ACE
inhibitors which is another common type
of blood pressure medications can
increase the concentration of these ACE
2 receptors on the surface of the cell
so how do you know if you're on an ARB
or an ACE inhibitor
typically a arby's and in ta n so you
might see this as losartan or urbis
Artin or candesartan these are all Tanz
they are angiotensin receptor blockers
we're going to talk more about what they
do so if it's true that they could
increase ace 2 levels it seems like it
will be common sense that if you have
more ace 2 receptors on the surface of
your cell now you've got more entry
points for the virus to infect your cell
ACE inhibitors they typically end in
pril so captopril and nalle' prill and
the list goes on those can also increase
potentially your ace 2 receptors and so
what do we do with patients who are on
ARVs and ACE inhibitors well it seems as
though people have a higher mortality
who have a history of hypertension and
so this has led to a number of articles
and a lot of social media to talk about
well should we get off of our
medications that we're taking for high
blood pressure so here is an article
that was sent to the Lancet was
published on March 11th 2020 and the
question is are patients with
hypertension and diabetes mellitus at
risk for kovat 19:00 infection and they
talk about the incidence of
cardiovascular diseases they talk about
the Czar's cuff virus and SARS
- and the ace - protein which is the
receptor for this and they talk about
how ACE inhibitors and ARBs
increase ace expression the increased
expression of ace - would facilitate
infection with kovat 19 we therefore
hypothesize that diabetes and
hypertension treatment with ACE to
stimulating drugs increases the risk of
developing severe and fatal kovat 19 now
this is only a hypothesis they say here
if this hypothesis were to be confirmed
it would lead to a conflict regarding
the treatment because ace 2 reduces
inflammation and has been suggested as a
potential new therapy for inflammatory
lung diseases cancer diabetes and
hypertension a further aspect that
should be investigated is the genetic
predisposition for an increased risk of
SARS cuff to infection which might have
to do with ace 2 polymorphisms they say
and here finally they say we suggest
that patients with cardiac diseases
hypertension or diabetes who are treated
with ACE to increasing drugs are at
higher risk for severe kovat 19
infection and therefore should be
monitored for ace 2 modulating
medications such as ACE inhibitors or
ARB s we did not find any evidence to
suggest that anti hypertensive calcium
channel blockers increase h2 expression
or activity therefore these could be
suitable alternative treatment in these
patients here we have an article a
correspondence to a very major journal
which is raising an alarm on millions of
patients who are on these medications
and saying that they hypothesize that
the patient could be at risk so
obviously this is raised quite a stir
and the question is is there any actual
truth to this so let's look and see what
the response has been well here is the
response from the European Society of
Cardiology they say here because of
social media related amplification these
patients taking their high blood
pressure medications have become
increasingly concerned and in some cases
stopped taking their ace or ARB
medications this is what the official
response is from the European Society
for cardiology the speculation about the
safety of ACE inhibitors or ARB
treatment in relation to kovat 19 does
not have a
scientific basis or evidence to support
it indeed there is evidence from studies
in animal suggesting that these
medications might be rather protective
against serious lung complications in
patients with kovat 19 infection but to
date there is no data in humans the
council on hypertension for the European
Society of Cardiology wish to highlight
the lack of any evidence supporting
harmful affective ACE inhibitors in ARB
in the context of pandemic Ovid 19
outbreak they strongly recommend that
physicians and patients should continue
treatment with their usual
antihypertensive therapy because there
is no clinical or scientific evidence to
suggest that treatment with ACE
inhibitors or ARB s should be
discontinued because of the kovat 19
infection so what is it which one of
these is correct to delve into the
intricacies of that we're gonna go into
some molecular biology at some point
we'll get a little complicated but not
too so bear with me as we go through a
detailed instruction on exactly what is
going on here with the SARS cub - virus
and the renin-angiotensin system to
understand this you first start off with
a hormone called angiotensinogen and
that is converted into angiotensin one
which will abbreviate a t1 and that is
done through a enzyme called renin that
is produced by the kidney
angiotensin 1 is then converted into
angiotensin 2 and that is done in the
lung by an enzyme called ace now ace is
in the lung it does convert angiotensin
1 to angiotensin 2 and we can inhibit
ace by giving someone an ACE inhibitor
and these are the medication that end in
prills
so captopril and lisinopril etc etc so
angiotensin 2 is a powerful
vasoconstrictor it also stimulates the
adrenal gland to make aldosterone which
has the action of lowering potassium and
increasing sodium concentration and
therefore increasing blood pressure
angiotensin 2 is a major dividing point
because there's two types of states that
one can have in the body so we'll call
this the low state and we'll call this
the high state on the cell membrane is a
component of proteins that are sitting
out on top of the cell membrane and one
of those is a stew and when there is not
a lot of angiotensin ii around it is
proposed angiotensin receptor 1 or a tr1
sits in the catalytic site of a stew now
as it turns out angiotensin 2 will be
converted by a stew into angiotensin one
7 and it's very important for you
understand
angiotensin 1 7 because angiotensin 1 7
causes vasodilation and decreases
inflammation that's a good thing it's
also possible that you could put and
have an angiotensin receptor blocker
that would block this and that is an a
RB so we've talked about angiotensin
receptor blockers and we've talked about
ACE inhibitors if you have high
angiotensin 2 this is the situation that
you get you still have a Stu but the
high levels of angiotensin 2 cause the
angiotensin receptor to come off of a
Stu and when that happens when
angiotensin 2 interacts with angiotensin
receptor 1 the result of that is
vasoconstriction increased blood
pressure increased vascular permeability
pulmonary edema and presumably a RDS
furthermore when there's high
angiotensin 2
hypothesis is that this opening in a
stew allows for the coronavirus with its
s protein to bind to a stew this binding
here also requires something called a
serine protease known as T M P r SS -
now that can be inhibited with something
called camest at mesylate and that is
undergoing trials right now
interestingly when you have high levels
of 82 this entire complex getting get
degraded into lysosomes so let's review
quickly
we've got angiotensinogen being
converted to angiotensin 1 by
renin-angiotensin 1 is converted to
angiotensin 2 by an ace enzyme ACE
inhibitors can prevent that from
happening if you have too much of
angiotensin 2 then what can happen is
this angiotensin receptor blocker
dissociates with ace 2 and it gets
activated to cause vasoconstriction
increase blood pressure permeability
pulmonary edema and a RDS that's exactly
what we don't like to see in these
situations in viral pneumonia however if
there are low levels of angiotensin 2
then what we see is that it gets
metabolized by ace 2 and that gets
converted into a vasodilator called
angiotensin 1 comma 7 also it looks as
though a arby's or angiotensin receptor
blockers can somehow keep this complex
together and keep that catalytic site
blocked by the resident ATR angiotensin
receptor and that can happen with
angiotensin receptor blockers if it's
high however this dissociation occurs
allowing the virus to potentially bind
according to the hypothesis and that
causes degradation so what do we see in
people who have no ace if we take away
all of their ace - as we're shown here
what happens well they've actually done
this in mice
they're able to breed mice where they
delete the gene responsible for making a
stew they're called knockouts double
knockouts mean they take it both on the
mother's side and the father's side so
when the mouse is born it has no ace -
whatsoever they've shown that these mice
have a resistance to being infected with
the virus because there's no receptor
but at the same time what they see in
these knockout mice is that they have
worse outcomes in viral pneumonia they
have decreased cardiac contractility and
they have increased levels of
angiotensin 2 which makes sense because
it's a stew which breaks down
angiotensin ii when there is a low
amount of it so these are in what we
call ace to knock out mice and these are
exactly the things that we're seeing in
patients who are infected with the
corona virus what they saw in a mouse
model of SARS cub from 2002 was that
there were decreased levels of ace - in
these viral models and they had normal
ACE levels but there was less ace -
levels
they also saw increased levels of
angiotensin 2 and when they gave these
mouse models ARB
and they gave them ace inhibitors this
actually improved the outcomes and I'll
show you the links to those studies in
the description below in a respiratory
syncytial virus case they actually took
recombinant ace - and gave it to these
mouse models and they found that it
improved outcomes so you can see
according to the animal hypothesis that
if you added an ACE inhibitor it would
block this ACE enzyme making sure that
this angiotensin 2 was on the low side
but what we may be seeing is that these
angiotensin levels are actually on the
high side and you would predict that if
angiotensin 2 levels were on the high
side you would expect there would be
aldosterone and low potassium and high
blood pressure and that's exactly what
they saw in very very sick kovat 19
patients is
they were hypokalemic which means low
potassium and the most critical of these
had higher blood pressure before they
crashed you can also see here how
keeping somebody on a angiotensin
receptor blocker according to this
hypothesis may improve this kind of a
situation leading to vasodilation and
anti inflammation and I want to
emphasize that while we have good data
in mice when we look at humans we don't
see these kinds of things happening at
least in the plasma in free-floating ace
we don't know what's going on at the
tissue level so it still may be
happening and so the thing I want to
stress here is that this is all
hypothesis based on piecing together
studies over the last 20 years that they
feel that this may be what's happening
and if you're interested in this kind of
research I'm going to put a bunch of
links in the description below that link
to the papers that talk about this but
suffice to say that at this point to go
out and say that we should be stopping
people on their ACE inhibitors and
stopping people in there on their ARVs
in my humble expert opinion as much as
you want to consider me an expert on
this I would say that the jury is out
and I believe I would come down on the
side of the statement from the European
Society for cardiology and saying we
really don't know at this point and we
have some animal studies which actually
show that they may be protective in this
case there's been a number of reports on
the deaths in kovat 19 that there are
infractions or their cardiac
contractility have been fine when they
come into the hospital but over a couple
of days of either viral myocarditis or
because of this situation that we're
seeing here that they're contractility
has dropped significantly as we would
expect when ace 2 levels go down so this
is something that needs to be addressed
and we don't know exactly what is going
to happen until we have those studies
the good news is according to what I
have seen in the last couple of days
there is research looking into starting
patients on angiotensin receptor
blockers or ARVs so that was a very long
explanation
over something that has come up very
recently I think we should continue to
delve into this receptor issue
especially when it comes to talking
about vaccines because ACE 2 is going to
play an extremely important role in the
future of treatment of Cova 19 thank you
for joining us
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