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A Mayo Clinic podcast for laboratory professionals, physicians, and students, hosted by Justin Kreuter, M.D., assistant professor of laboratory medicine and pathology at Mayo Clinic, featuring educational topics and insightful takeaways to apply in your practice.
(bright upbeat music)
- This is "Lab Medicine Rounds",
a curated podcast for physicians,
laboratory professionals, and students.
I'm your host, Justin Kreuter,
a Transfusion Medicine Pathologist
and Assistant Professor
of Laboratory Medicine
and Pathology at Mayo Clinic.
Today we're rounding with Dr. Allan Jaffe,
Wayne and Catherine Prisil,
professor of cardiovascular
disease research,
professor of laboratory
medicine and pathology
and professor of medicine
in the Department of Cardiovascular
Diseases at Mayo Clinic
to talk about cardiac troponins
and checkpoint inhibitors.
Thanks for joining us today Dr. Jaffe.
- My pleasure to be there.
- So this is kind of an a complex topic.
Could you kind of give us
a kind of an introduction,
background for this concept
of checkpoint inhibitors
and cardiac troponins?
- Sure let's start by backing up
and just talking about
checkpoint inhibitors.
Basically what they do is that
they increase the sensitivity
of the immune system by
inhibiting certain steps
so that antigens that may not in the past
have been detected, are
detected and processed.
And what that allows is the
ability of the abnormal antigens
that are associated with
cancer to be detected
and to have an immune
response mounted against them.
And that's why they're effective,
and they're revolutionizing
cancer therapy.
They're used probably at the
Mayo Clinic, at least 6,000,
6,000 patients per year as an estimate.
So they're very commonly used
and they cause marked improvement
in mortality and morbidity
in patients with a variety of cancers.
The downside of immune
checkpoint inhibitors however,
is there's some antigens that
may not wanna be processed,
so that immune checkpoint inhibitors
can cause a variety of
autoimmune phenomena
that you prefer to avoid.
The most common is probably
arthritis and arthralgias,
which may occur in anywhere
from 10 to 15 maybe even 20%
of people getting these
checkpoint inhibitors
and usually is easily treated.
And there are a variety of others
that involve almost every organ system.
The most dreaded of these
is if it involves the heart
and can cause myocarditis.
And we don't know the exact incidents
of myocarditis being honest,
because we only see the
critically ill patients
where there is a reason
to do either a biopsy
or a magnetic resonance imaging
which is the way the diagnosis
is most often confirmed.
So it said that maybe
it's 1% of the people
who get immune checkpoint inhibitors,
but I would bet if you
could do surveillance
on a larger group, that
it's probably more common
in that there are low grade
types of presentations
that we don't really appreciate.
Nonetheless, the sick
patients get in the hospital,
and that's where troponin
becomes an important adjunct
both for diagnosis and therapy.
Often, it is the troponin
that calls attention
to the fact that there may be
cardiovascular involvement.
This gets a little bit complicated
because as I'm sure you're aware,
and we've probably talked to this audience
about in the past,
patients with malignancies
not only can have cardiovascular
disease in their past,
and that can give you an elevated troponin
if you have some structural heart disease,
whether it's heart failure or
some sort of cardiomyopathy,
or poorly controlled hypertension.
But in addition, cancer
may in and of itself
cause some cardiovascular abnormalities.
And so having an elevated
troponin in and of itself
doesn't tell you that you necessarily
have immune checkpoint
inhibitor myocarditis,
but it might call attention
in the appropriate person
in whom it's unexpected to at
least look for that diagnosis.
The most, the best way
to make the diagnosis
is with either biopsy
or most often nowadays
we use magnetic resonance imaging
which gives one a pretty good signal.
And then the issue becomes,
okay, how do we use troponin
and how do we follow these patients?
Because therapy becomes critical.
Usually it's with high doses of steroids
that become tapered but there
are other therapies as well
that impact the immune system
that people want to know about as well.
The tension in this area comes about,
however diagnostically with troponin
for a variety of reasons, there's several.
The first is,
that although you can
have an elevated troponin
and for example at the Mayo Clinic
we use cardiac troponin T,
and that may lead you to the diagnosis.
There are other reasons for proponent T
being elevated as well.
Those include the things we talked about
just a couple of minutes ago
in the background segment
of prior cardiovascular disease,
or even cancer related
cardiovascular disease.
But in addition, it turns
out that we've noticed here
and this has been confirmed
in the literature as well,
that there frequently are
elevations of cardiac troponin T
in the absence of overt myocarditis
or when we think the
myocarditis is improving.
And our thought about that originally now,
partially confirmed in the literature
which I'll mention in a moment,
is that cardiac troponin
T can be repressed
in damaged skeletal muscle.
We showed that some years ago.
It's been well-documented
in a variety of different
studies that that can occur.
If you're a troponin T
advocate, you would say,
"Well, they've never
sequenced the exact sequence
of the protein and you're
making these assumptions
based on antibody binding and on mRNA
and maybe that's not perfect."
No question, that's a
legitimate criticism.
But I think the data are now pretty clear
that cardiac troponin T can be elevated
to skeletal muscle disease and myositis
is a almost a 100% concomitant
when one has myocarditis.
And maybe there's a hint there,
to the etiology of the syndrome.
We don't know that yet
because we don't know
which antigen or antigens
are responsible for causing the disease.
But the consequence of that is,
that we've seen patients here
who have elevated troponin T,
we treat them, we think the
myocarditis is under control,
and in some instances improving by MRI,
and the MRI findings of myocarditis
can persist for a long time,
but they can also go away rapidly.
So sometimes they go away rapidly
and you say, "We're home free."
But the troponin T is
still markedly elevated.
That's likely due to the fact
that the process is still
ongoing in skeletal muscle
and causing a very robust increase
in troponin T due to myositis.
This was recently partially confirmed
in a large registry trial, it
was published in circulation
from the group at Heidelberg.
And what they did in
these patients who had,
they proven immune checkpoint
inhibitor myocarditis,
that is to say they had a biopsy or an MRI
that was considered diagnostic.
They then looked over time
and they found the same persistence
of increases in troponin T
even when the heart seemed
to be getting better.
So they biopsied skeletal muscle
and we're able to show the repression
of the messenger RNA for a
cardiac troponin isoform.
Now this doesn't prove it,
it's not sequenced as
the some would argue.
So what we've done here at Mayo,
and initially we thought this
would be a perfect strategy
and it may turn out not to
be a totally perfect one,
is when we saw these sorts of patients
we would then measure cardiac troponin I,
we have the ability and have
additional high sensitivity
cardiac troponin assays including
cardiac troponin I assays,
and often the troponin
I assay would be normal.
And so you say, "Okay,
we've done a good job
treating the myocarditis."
And around here, at some
points in time people said,
"Oh, we shouldn't even
get troponin 10 anymore.
Let's just get troponin I."
Recent data makes that
a little more suspect,
because the same group that
I mentioned in Heidelberg
was doing a registry study
and they published the data
that suggested that in patients
who were well documented
to have myocarditis by
either MRI or biopsy,
that cardiac troponin T was elevated
in about 93 or 94% of them,
but it was only 60% who had an elevation
in cardiac troponin I.
Now, this was a dirty
study in the sense that
there were multiple different I assays,
multiple different cutoffs used
that made it very hard
to sort all of this.
But it raised the question
as to whether or not
one could have cardiac
involvement with myocarditis
and not have a troponin I signal.
And there certainly are reasons
you could think that might occur.
One is maybe they didn't have myocarditis
that was ongoing in the first place.
As I mentioned, the findings
of myocarditis can persist,
so maybe this was not the right diagnosis.
Secondly, there were
heterogeneity of assays
that some of which used the right cutoff,
some of which didn't,
and none of that was as ideally
provided in the manuscript
as you would like.
But in point of fact,
you can't take a study
of many hundreds of patients
and show the cardiac troponin
assay for each one of them.
But it raises the question
as to whether or not
the troponin I could miss things,
which could be related to the fact that
there are many fragments
of cardiac troponin I and T
for that matter.
It turns out that for the T assay,
the epitopes for detection
are close to one another,
two to six amino acids apart.
So that even if you cleave things up
into the tiniest little fragments,
you end up with a persistent signal.
On the other hand, for cardiac troponin I,
the antibodies are often 20,
30, 40, 50 amino acids apart.
So as you begin to cleave up the fragments
which we know occurs,
then perhaps you could lose the signal.
And we have hypothesized,
several of us in book chapters,
that perhaps the fragments
that are present in a heart attack,
which is the ones we know and love and use
are different in the patient
who might have an inflammatory
reason like a myocarditis.
So it's at least a possibility.
If that's true, then perhaps the fact
that the troponin I
goes down with treatment
and looks like it tracks with the heart
may partially be correct
and partially be related
to the fact that it doesn't
have as high sensitivity
for detecting the disease
as might be ideal.
This becomes important in the fact
that the paper that I mentioned
from Heidelberg suggested
that when one had increases
in troponin T that persisted,
that the prognosis was
related to that persistence
to a greater extent than
other clinical parameters.
The likely explanation
for that, I would argue,
and I think, and this is what they argued
as well by the way, was that,
there is a skeletal muscle component
and the fact that it is
persisting as documented
with increases in cardiac proponent T,
means that the process
that undergirds this is still ongoing.
And if that were to be the case,
then one could be seduced
into thinking one is home free
whereas given the
process is still ongoing,
it may well be that the troponin T signal
is a key one to alert
people to the fact that
more treatment is necessary.
- Wow, so you're really
kind of highlighting
the complexity of this issue.
And I think for our audience
just how this is really a very active,
dynamic, an evolving area,
and it sort of sounds like
for the laboratory medicine component
of our audience right?
You're highlighting I guess
in my mind about, you know
if I get asked about somebody
who has an elevated troponin
and otherwise not, you
know, was a surprise
to ask or inquire about
checkpoint inhibitor therapy.
And also you're highlighting I guess
some of the changes on
what might we do in a lab.
So if I could ask you
just to maybe re-highlight
for the laboratory medicine listeners
how might we go about supporting
the clinical practice in these patients
that are kind of facing this issue?
- A couple of suggestions.
First of all, we do measure
cardiac troponin I and
T in these patients.
Now, it's intrinsically
a little bit difficult
because you don't want two high
sensitivity troponin assays
with totally different metrics
floating around your institution.
So we make make it very special orderable
only in the special circumstance
where this information
is necessary, number one.
Number two, and I didn't
mention this but I will,
we're in an environment
now, where we're stimulating
immunoglobulins in
hundreds of different ways,
both from vaccinations that we all,
and I'm not criticizing vaccinations,
but increases immunoglobulins
and checkpoint inhibitors
which increase the immune response.
And we have seen some patients
who have had false positive increases
because of so-called macro-troponins
which are conglomerates of
troponin and immunoglobulin.
Now mostly they occur
with cardiac troponin I
to a greater extent than
T, but there certainly
are such circumstances
where T is involved.
And there is a recent abstract
in European Society
Cardiology that suggested
that even when these were
troponin I macro-troponins,
that they had an influence
on troponin T as well,
likely because of inter-digitation
with the TIC complex,
one of the common fragments that exist.
So two or three things
that the lab can do.
Number one is, if indeed
you're a large lab
and if you're a small facility,
you may not be able to do this,
but you could work out an
arrangement with a larger lab
to measure cardiac troponin
I in the subset of patients
where it becomes clinically important.
If that's, and that is helpful.
Now, nothing's a 100%,
so you need to be careful
not to simply say, "Ah, I'm done."
If you get reassurance
with cardiac troponin I,
and you're using T,
similarly, you need to be circumspective,
if you get troponin I, that is normal,
and you get an elevated T, or vice versa.
So you need to be careful.
But I would argue that making
arrangements to test for both
in this unique circumstance
that should occur mostly in quaternary,
tertiary and quaternary referral centers
is probably worthwhile.
Secondly, we ought to be
ready to do troubleshooting
for the analytic false positives,
whether they're heterofiles
or macro-troponins.
The easiest way to do that
often is to have a second assay.
And I think most of us would say
if the second assay comports
better to the clinical circumstance,
perhaps that's adequate
without doing a lot of
additional investigation.
Although, several of us
have written guidance papers
about how to do those
eventual investigations
when and if they are necessary.
Finally, the field really needs
a much more systematic approach.
For example, is cardiac
troponin I really not elevated
in a bunch of patients with myocarditis?
It would be nice that if
the study that I mentioned
had been able to do troponin
I and T and all the patients,
had the same assay with the same metrics,
and so we could answer
that question definitively
that would be helpful.
We then need to figure out
whether or not if the
myocarditis part of this abates
and we're left with the myositis,
whether or not we need to
continue therapy at a same level,
a different level,
what are the appropriate
therapeutic responses?
So the laboratory can help by
giving clinicians the tools
but there's a clinical part of this
that depends on the
judgment of the clinicians
and eventually additional research.
- So it seems like to go
from here, you say research,
I'm sure our student listeners' eyes
perk up for opportunities.
You're highlighting a
role for the laboratory
in going forward as well
as the clinical team.
- Absolutely.
- So all three of those groups
are working together to tackle
some of these questions,
is there one of them that's
really you think top of mind
that really stands over
and above the others
in your mind right now?
- Well I think one of the
things that we don't have
and haven't had, and we're
gonna try and remedy that,
is to know what people start at.
So for example, you have,
God forbid a cancer,
and the question is what
are your troponin values?
Are they elevated?
Because it may well be that
in some of these instances
we're responding to chronic increases
and it would be important to know that.
Secondly, when subsequently
if we have baseline values,
we'd be able to say, "Well,
yes, troponin T is elevated
but you know, I is pretty elevated too
compared to what it was at baseline,
where it was very very low",
for example, or vice versa.
So that it would be very important
to add that component to it.
Finally, as we get better at
troubleshooting the analytics,
eventually it would be
ideal to develop techniques
that could look for some of these
analytic problems on our analyzers.
And there are several companies
that are working on such solutions,
which would be very helpful.
Not for everybody, not
for every single sample,
but for those where there
is a real clinical need
to figure out what's going on.
- We've been rounding with Dr. Jaffe
talking about cardiac troponins
and checkpoint inhibitors.
Thanks for taking your time
to talk about this with us.
- Been my pleasure.
I hope it's been clear and helpful.
- Absolutely, to all of our listeners
thank you for joining us today.
We invite you to share your
thoughts and suggestions
via email to mcleducation@mayo.edu.
If you've enjoyed this
podcast please subscribe
until our next rounds together,
we encourage you to continue
to connect lab medicine
and the clinical practice through
educational conversations.
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