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- 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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