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(bright upbeat music)

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- This is "Lab Medicine Rounds",

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a curated podcast for physicians,

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laboratory professionals, and students.

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I'm your host, Justin Kreuter,

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a Transfusion Medicine Pathologist

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and Assistant Professor
of Laboratory Medicine

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and Pathology at Mayo Clinic.

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Today we're rounding with Dr. Allan Jaffe,

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Wayne and Catherine Prisil,

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professor of cardiovascular
disease research,

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professor of laboratory
medicine and pathology

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and professor of medicine

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in the Department of Cardiovascular
Diseases at Mayo Clinic

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to talk about cardiac troponins
and checkpoint inhibitors.

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Thanks for joining us today Dr. Jaffe.

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- My pleasure to be there.

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- So this is kind of an a complex topic.

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Could you kind of give us
a kind of an introduction,

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background for this concept
of checkpoint inhibitors

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and cardiac troponins?

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- Sure let's start by backing up

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and just talking about
checkpoint inhibitors.

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Basically what they do is that
they increase the sensitivity

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of the immune system by
inhibiting certain steps

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so that antigens that may not in the past

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have been detected, are
detected and processed.

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And what that allows is the
ability of the abnormal antigens

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that are associated with
cancer to be detected

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and to have an immune
response mounted against them.

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And that's why they're effective,

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and they're revolutionizing
cancer therapy.

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They're used probably at the
Mayo Clinic, at least 6,000,

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6,000 patients per year as an estimate.

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So they're very commonly used

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and they cause marked improvement

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in mortality and morbidity

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in patients with a variety of cancers.

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The downside of immune
checkpoint inhibitors however,

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is there's some antigens that
may not wanna be processed,

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so that immune checkpoint inhibitors

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can cause a variety of
autoimmune phenomena

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that you prefer to avoid.

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The most common is probably
arthritis and arthralgias,

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which may occur in anywhere
from 10 to 15 maybe even 20%

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of people getting these
checkpoint inhibitors

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and usually is easily treated.

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And there are a variety of others

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that involve almost every organ system.

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The most dreaded of these

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is if it involves the heart
and can cause myocarditis.

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And we don't know the exact incidents

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of myocarditis being honest,

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because we only see the
critically ill patients

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where there is a reason
to do either a biopsy

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or a magnetic resonance imaging

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which is the way the diagnosis
is most often confirmed.

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So it said that maybe
it's 1% of the people

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who get immune checkpoint inhibitors,

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but I would bet if you
could do surveillance

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on a larger group, that
it's probably more common

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in that there are low grade
types of presentations

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that we don't really appreciate.

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Nonetheless, the sick
patients get in the hospital,

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and that's where troponin
becomes an important adjunct

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both for diagnosis and therapy.

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Often, it is the troponin
that calls attention

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to the fact that there may be
cardiovascular involvement.

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This gets a little bit complicated

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because as I'm sure you're aware,

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and we've probably talked to this audience

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about in the past,
patients with malignancies

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not only can have cardiovascular
disease in their past,

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and that can give you an elevated troponin

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if you have some structural heart disease,

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whether it's heart failure or
some sort of cardiomyopathy,

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or poorly controlled hypertension.

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But in addition, cancer
may in and of itself

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cause some cardiovascular abnormalities.

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And so having an elevated
troponin in and of itself

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doesn't tell you that you necessarily

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have immune checkpoint
inhibitor myocarditis,

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but it might call attention
in the appropriate person

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in whom it's unexpected to at
least look for that diagnosis.

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The most, the best way
to make the diagnosis

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is with either biopsy
or most often nowadays

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we use magnetic resonance imaging

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which gives one a pretty good signal.

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And then the issue becomes,

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okay, how do we use troponin

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and how do we follow these patients?

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Because therapy becomes critical.

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Usually it's with high doses of steroids

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that become tapered but there
are other therapies as well

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that impact the immune system

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that people want to know about as well.

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The tension in this area comes about,

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however diagnostically with troponin

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for a variety of reasons, there's several.

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The first is,

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that although you can
have an elevated troponin

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and for example at the Mayo Clinic

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we use cardiac troponin T,

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and that may lead you to the diagnosis.

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There are other reasons for proponent T

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being elevated as well.

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Those include the things we talked about

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just a couple of minutes ago
in the background segment

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of prior cardiovascular disease,

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or even cancer related
cardiovascular disease.

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But in addition, it turns
out that we've noticed here

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and this has been confirmed
in the literature as well,

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that there frequently are
elevations of cardiac troponin T

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in the absence of overt myocarditis

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or when we think the
myocarditis is improving.

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And our thought about that originally now,

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partially confirmed in the literature

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which I'll mention in a moment,

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is that cardiac troponin
T can be repressed

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in damaged skeletal muscle.

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We showed that some years ago.

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It's been well-documented

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in a variety of different
studies that that can occur.

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If you're a troponin T
advocate, you would say,

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"Well, they've never
sequenced the exact sequence

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of the protein and you're
making these assumptions

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based on antibody binding and on mRNA

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and maybe that's not perfect."

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No question, that's a
legitimate criticism.

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But I think the data are now pretty clear

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that cardiac troponin T can be elevated

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to skeletal muscle disease and myositis

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is a almost a 100% concomitant
when one has myocarditis.

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And maybe there's a hint there,

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to the etiology of the syndrome.

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We don't know that yet

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because we don't know
which antigen or antigens

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are responsible for causing the disease.

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But the consequence of that is,

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that we've seen patients here
who have elevated troponin T,

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we treat them, we think the
myocarditis is under control,

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and in some instances improving by MRI,

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and the MRI findings of myocarditis

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can persist for a long time,

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but they can also go away rapidly.

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So sometimes they go away rapidly

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and you say, "We're home free."

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But the troponin T is
still markedly elevated.

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That's likely due to the fact

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that the process is still
ongoing in skeletal muscle

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and causing a very robust increase

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in troponin T due to myositis.

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This was recently partially confirmed

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in a large registry trial, it
was published in circulation

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from the group at Heidelberg.

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And what they did in
these patients who had,

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they proven immune checkpoint
inhibitor myocarditis,

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that is to say they had a biopsy or an MRI

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that was considered diagnostic.

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They then looked over time

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and they found the same persistence

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of increases in troponin T

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even when the heart seemed
to be getting better.

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So they biopsied skeletal muscle

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and we're able to show the repression

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of the messenger RNA for a
cardiac troponin isoform.

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Now this doesn't prove it,

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it's not sequenced as
the some would argue.

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So what we've done here at Mayo,

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and initially we thought this
would be a perfect strategy

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and it may turn out not to
be a totally perfect one,

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is when we saw these sorts of patients

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we would then measure cardiac troponin I,

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we have the ability and have
additional high sensitivity

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cardiac troponin assays including
cardiac troponin I assays,

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and often the troponin
I assay would be normal.

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And so you say, "Okay,
we've done a good job

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treating the myocarditis."

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And around here, at some
points in time people said,

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"Oh, we shouldn't even
get troponin 10 anymore.

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Let's just get troponin I."

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Recent data makes that
a little more suspect,

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because the same group that
I mentioned in Heidelberg

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was doing a registry study
and they published the data

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that suggested that in patients
who were well documented

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to have myocarditis by
either MRI or biopsy,

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that cardiac troponin T was elevated

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in about 93 or 94% of them,

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but it was only 60% who had an elevation

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in cardiac troponin I.

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Now, this was a dirty
study in the sense that

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there were multiple different I assays,

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multiple different cutoffs used

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that made it very hard
to sort all of this.

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But it raised the question
as to whether or not

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one could have cardiac
involvement with myocarditis

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and not have a troponin I signal.

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And there certainly are reasons

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you could think that might occur.

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One is maybe they didn't have myocarditis

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that was ongoing in the first place.

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As I mentioned, the findings
of myocarditis can persist,

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so maybe this was not the right diagnosis.

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Secondly, there were
heterogeneity of assays

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that some of which used the right cutoff,

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some of which didn't,

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and none of that was as ideally
provided in the manuscript

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as you would like.

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But in point of fact,
you can't take a study

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of many hundreds of patients

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and show the cardiac troponin
assay for each one of them.

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But it raises the question
as to whether or not

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the troponin I could miss things,

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which could be related to the fact that

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there are many fragments
of cardiac troponin I and T

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for that matter.

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It turns out that for the T assay,

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the epitopes for detection
are close to one another,

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two to six amino acids apart.

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So that even if you cleave things up

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into the tiniest little fragments,

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you end up with a persistent signal.

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On the other hand, for cardiac troponin I,

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the antibodies are often 20,
30, 40, 50 amino acids apart.

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So as you begin to cleave up the fragments

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which we know occurs,

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then perhaps you could lose the signal.

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And we have hypothesized,
several of us in book chapters,

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that perhaps the fragments

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that are present in a heart attack,

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which is the ones we know and love and use

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are different in the patient

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who might have an inflammatory
reason like a myocarditis.

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So it's at least a possibility.

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If that's true, then perhaps the fact

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that the troponin I
goes down with treatment

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and looks like it tracks with the heart

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may partially be correct
and partially be related

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to the fact that it doesn't
have as high sensitivity

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for detecting the disease
as might be ideal.

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This becomes important in the fact

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that the paper that I mentioned
from Heidelberg suggested

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that when one had increases
in troponin T that persisted,

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that the prognosis was
related to that persistence

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to a greater extent than
other clinical parameters.

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The likely explanation
for that, I would argue,

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and I think, and this is what they argued

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as well by the way, was that,

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there is a skeletal muscle component

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and the fact that it is
persisting as documented

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with increases in cardiac proponent T,

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means that the process

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that undergirds this is still ongoing.

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And if that were to be the case,

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then one could be seduced
into thinking one is home free

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whereas given the
process is still ongoing,

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it may well be that the troponin T signal

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is a key one to alert
people to the fact that

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more treatment is necessary.

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- Wow, so you're really
kind of highlighting

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the complexity of this issue.

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And I think for our audience

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just how this is really a very active,

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dynamic, an evolving area,

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and it sort of sounds like

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for the laboratory medicine component

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of our audience right?

268
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You're highlighting I guess
in my mind about, you know

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if I get asked about somebody
who has an elevated troponin

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and otherwise not, you
know, was a surprise

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to ask or inquire about
checkpoint inhibitor therapy.

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And also you're highlighting I guess

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some of the changes on
what might we do in a lab.

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So if I could ask you
just to maybe re-highlight

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for the laboratory medicine listeners

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00:15:21,180 --> 00:15:24,826
how might we go about supporting

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the clinical practice in these patients

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that are kind of facing this issue?

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- A couple of suggestions.

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First of all, we do measure

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cardiac troponin I and
T in these patients.

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Now, it's intrinsically
a little bit difficult

283
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because you don't want two high
sensitivity troponin assays

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with totally different metrics

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floating around your institution.

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So we make make it very special orderable

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only in the special circumstance

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where this information
is necessary, number one.

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Number two, and I didn't
mention this but I will,

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we're in an environment
now, where we're stimulating

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immunoglobulins in
hundreds of different ways,

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both from vaccinations that we all,

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and I'm not criticizing vaccinations,

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but increases immunoglobulins
and checkpoint inhibitors

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which increase the immune response.

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And we have seen some patients

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who have had false positive increases

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because of so-called macro-troponins

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which are conglomerates of
troponin and immunoglobulin.

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Now mostly they occur
with cardiac troponin I

301
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to a greater extent than
T, but there certainly

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are such circumstances
where T is involved.

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And there is a recent abstract

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in European Society
Cardiology that suggested

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that even when these were
troponin I macro-troponins,

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that they had an influence
on troponin T as well,

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likely because of inter-digitation
with the TIC complex,

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one of the common fragments that exist.

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So two or three things
that the lab can do.

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Number one is, if indeed
you're a large lab

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and if you're a small facility,

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you may not be able to do this,

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but you could work out an
arrangement with a larger lab

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to measure cardiac troponin
I in the subset of patients

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where it becomes clinically important.

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If that's, and that is helpful.

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Now, nothing's a 100%,
so you need to be careful

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not to simply say, "Ah, I'm done."

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If you get reassurance
with cardiac troponin I,

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and you're using T,

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00:17:53,160 --> 00:17:55,920
similarly, you need to be circumspective,

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if you get troponin I, that is normal,

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and you get an elevated T, or vice versa.

324
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So you need to be careful.

325
00:18:04,830 --> 00:18:08,970
But I would argue that making
arrangements to test for both

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in this unique circumstance

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00:18:11,370 --> 00:18:14,523
that should occur mostly in quaternary,

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tertiary and quaternary referral centers

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00:18:19,050 --> 00:18:21,060
is probably worthwhile.

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00:18:21,060 --> 00:18:23,820
Secondly, we ought to be
ready to do troubleshooting

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for the analytic false positives,

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00:18:25,980 --> 00:18:30,090
whether they're heterofiles
or macro-troponins.

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00:18:30,090 --> 00:18:35,090
The easiest way to do that
often is to have a second assay.

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00:18:35,490 --> 00:18:37,230
And I think most of us would say

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00:18:37,230 --> 00:18:39,570
if the second assay comports

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00:18:39,570 --> 00:18:44,400
better to the clinical circumstance,
perhaps that's adequate

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00:18:44,400 --> 00:18:47,640
without doing a lot of
additional investigation.

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00:18:47,640 --> 00:18:51,180
Although, several of us
have written guidance papers

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00:18:51,180 --> 00:18:54,424
about how to do those
eventual investigations

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00:18:54,424 --> 00:18:56,703
when and if they are necessary.

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Finally, the field really needs

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00:19:01,920 --> 00:19:04,353
a much more systematic approach.

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00:19:05,280 --> 00:19:09,630
For example, is cardiac
troponin I really not elevated

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00:19:09,630 --> 00:19:12,480
in a bunch of patients with myocarditis?

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00:19:12,480 --> 00:19:16,440
It would be nice that if
the study that I mentioned

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00:19:16,440 --> 00:19:21,440
had been able to do troponin
I and T and all the patients,

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00:19:21,660 --> 00:19:24,603
had the same assay with the same metrics,

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00:19:25,440 --> 00:19:28,620
and so we could answer
that question definitively

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00:19:28,620 --> 00:19:30,570
that would be helpful.

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00:19:30,570 --> 00:19:32,880
We then need to figure out

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00:19:32,880 --> 00:19:37,880
whether or not if the
myocarditis part of this abates

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00:19:38,160 --> 00:19:41,280
and we're left with the myositis,

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00:19:41,280 --> 00:19:45,420
whether or not we need to
continue therapy at a same level,

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00:19:45,420 --> 00:19:47,220
a different level,

355
00:19:47,220 --> 00:19:50,670
what are the appropriate
therapeutic responses?

356
00:19:50,670 --> 00:19:55,590
So the laboratory can help by
giving clinicians the tools

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but there's a clinical part of this

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00:19:58,770 --> 00:20:01,890
that depends on the
judgment of the clinicians

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00:20:01,890 --> 00:20:04,470
and eventually additional research.

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00:20:04,470 --> 00:20:08,940
- So it seems like to go
from here, you say research,

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00:20:08,940 --> 00:20:11,400
I'm sure our student listeners' eyes

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perk up for opportunities.

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00:20:13,984 --> 00:20:17,670
You're highlighting a
role for the laboratory

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00:20:17,670 --> 00:20:21,123
in going forward as well
as the clinical team.

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00:20:22,112 --> 00:20:25,170
- Absolutely.
- So all three of those groups

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00:20:25,170 --> 00:20:30,170
are working together to tackle
some of these questions,

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00:20:30,270 --> 00:20:33,175
is there one of them that's
really you think top of mind

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00:20:33,175 --> 00:20:36,330
that really stands over
and above the others

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00:20:36,330 --> 00:20:37,740
in your mind right now?

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00:20:37,740 --> 00:20:40,110
- Well I think one of the
things that we don't have

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00:20:40,110 --> 00:20:44,730
and haven't had, and we're
gonna try and remedy that,

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00:20:44,730 --> 00:20:48,030
is to know what people start at.

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00:20:48,030 --> 00:20:51,900
So for example, you have,
God forbid a cancer,

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00:20:51,900 --> 00:20:55,860
and the question is what
are your troponin values?

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00:20:55,860 --> 00:20:57,300
Are they elevated?

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00:20:57,300 --> 00:21:00,990
Because it may well be that
in some of these instances

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00:21:00,990 --> 00:21:05,130
we're responding to chronic increases

378
00:21:05,130 --> 00:21:07,470
and it would be important to know that.

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00:21:07,470 --> 00:21:12,300
Secondly, when subsequently
if we have baseline values,

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00:21:12,300 --> 00:21:17,300
we'd be able to say, "Well,
yes, troponin T is elevated

381
00:21:17,460 --> 00:21:20,340
but you know, I is pretty elevated too

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00:21:20,340 --> 00:21:22,260
compared to what it was at baseline,

383
00:21:22,260 --> 00:21:26,550
where it was very very low",
for example, or vice versa.

384
00:21:26,550 --> 00:21:28,860
So that it would be very important

385
00:21:28,860 --> 00:21:32,670
to add that component to it.

386
00:21:32,670 --> 00:21:37,670
Finally, as we get better at
troubleshooting the analytics,

387
00:21:38,760 --> 00:21:43,410
eventually it would be
ideal to develop techniques

388
00:21:43,410 --> 00:21:44,940
that could look for some of these

389
00:21:44,940 --> 00:21:48,183
analytic problems on our analyzers.

390
00:21:49,020 --> 00:21:50,910
And there are several companies

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00:21:50,910 --> 00:21:53,700
that are working on such solutions,

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00:21:53,700 --> 00:21:56,400
which would be very helpful.

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00:21:56,400 --> 00:22:00,180
Not for everybody, not
for every single sample,

394
00:22:00,180 --> 00:22:03,450
but for those where there
is a real clinical need

395
00:22:03,450 --> 00:22:05,643
to figure out what's going on.

396
00:22:07,230 --> 00:22:09,090
- We've been rounding with Dr. Jaffe

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00:22:09,090 --> 00:22:12,720
talking about cardiac troponins
and checkpoint inhibitors.

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00:22:12,720 --> 00:22:16,260
Thanks for taking your time
to talk about this with us.

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00:22:16,260 --> 00:22:17,220
- Been my pleasure.

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00:22:17,220 --> 00:22:21,330
I hope it's been clear and helpful.

401
00:22:21,330 --> 00:22:23,160
- Absolutely, to all of our listeners

402
00:22:23,160 --> 00:22:24,420
thank you for joining us today.

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00:22:24,420 --> 00:22:27,180
We invite you to share your
thoughts and suggestions

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00:22:27,180 --> 00:22:31,380
via email to mcleducation@mayo.edu.

405
00:22:31,380 --> 00:22:33,900
If you've enjoyed this
podcast please subscribe

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00:22:33,900 --> 00:22:35,730
until our next rounds together,

407
00:22:35,730 --> 00:22:38,877
we encourage you to continue
to connect lab medicine

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00:22:38,877 --> 00:22:42,542
and the clinical practice through
educational conversations.

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00:22:42,542 --> 00:22:45,792
(bright upbeat music)