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Tune into our bi-monthly podcast where we interview experts in the field to broaden the awareness of new HCM studies & advancements!
ANNOUNCER: You are listening to In the Thick of
It, a podcast from the HCM Society, where we interview
experts in the hypertrophic cardiomyopathy field
to broaden the awareness of new HCM studies and
advancements. In this episode, Dr. Robin Bride
and Dr. Bradley Lander will be interviewing each
presenting author of the selected abstracts to
tell us more about their HCM research. These abstract
presentations were selected to encore at the 2023
HCMS Scientific Sessions on October 6. Join us
as three brilliant minds unravel the latest breakthroughs
within HCM studies. This episode is your gateway
to cutting edge research. Stay tuned for a journey
through innovation and discovery in the world
of healthcare. Let's get in the thick of it. Dr.
Robin Bride had the pleasure of speaking with
our first presenter, Dr. Saad Al-Saddi, who is
a Senior Associate Consultant at Mayo Clinic in
Rochester. He's joining us today to talk about
his presentation on risk factors associated with
ICD discharges in patients with hypertrophic cardiomyopathy.
DR. BRYDE: So Dr. El-Sawadi, thank you so much
for being here today. It's very exciting work
that you are presenting, of course, very important
with the patients with. Hypertrophic cardiomyopathy.
One of the biggest things that clinicians struggle
with is really risk stratification for who needs
an ICD. For sudden cardiac death prevention. So
very important that we. Do this appropriately
and continue to grow our knowledge base on this
forefront. So I will hand it over to you. Tell
us a little bit about this study.
DR. ALSIDAWI: Thank you, Robin. Thanks for having
me again. So just kind of summarize the study
for you. The goal of the study was to assess how
do patients do after they get an ICD, either for
secondary or primary prevention. For sudden cardiac
death in patients who have hypertrophic cardiomyopathy.
So. We took our database here at Mayo Clinic in
Arizona, and then what we did is we analyzed the
data over. Period of time to look at patients
who have an ICD. And had an MRI so we can get
their late-getting and enhancement data at the
same time. And then we broke down the data by
the current indication in the ACC AHA guidelines.
For secondary and primary prevention for sudden
cardiac death. We wanted to see how each factor
play a role and then how, when we interact these
factors together, mainly the LGE. With each of
the primary prevention factor, how does that?
Synergistic effect play a role in the risk stratification.
So overall, we had 134 patients in our database.
These are patients who have an ICD. And have a
cardiac MRI done within a year before receiving
their ICD. In 114 of these patients, we had...
Clear LGE data. And we had one of our MRI readers
go back and quantify all the LGEs on these MRIs.
And then we followed this patient longitudinally.
And so. And looked at who received an ICD discharge
appropriately. Will therefore sustain ventricular
tachycardia or ventricular fibrillation. We define
that as a sudden cardiac death event or an aborted
sudden cardiac death event. What we did is a univariate
analysis as well as a bivariate Cook's regression
analysis to study the interaction between each
factor. And delete Get-A-Linium enhancement. Now
I need to point out that this is a relatively
smaller study where we're doing a larger study
on a larger scale now. That include all the Mayo
Clinic sites. But we wanted to just present this
as the early signal. From this study that we were
able to see. So. First thing we saw in our results
that patients who received an ICD for secondary
prevention. Had a significantly increased hazard
ratio of receiving a shock. That was eight times
higher. Then patients who received it for primary
prevention. So that's clearly a class one recommendation
in the guidelines and appropriately so based on
what we found in our study. Now, when we looked
at the primary prevention, Reasons to receive
an ICD including unexplained syncope, family history
of sudden death, septal thickness, of over 30
millimeters. In addition to apical aneurysm. Now
all our patients had an EF over 50%. So we didn't
use that as a factor. In addition to non-sustained
ventricular tachycardia on an ambulatory monitor.
None of these by themselves, when we looked at
them by themselves, increased the hazard ratio
of receiving a shock. There was a slight increase
in patients who received the ICD for non-sustained
ventricular tachycardia and were very strict in.
Selecting these patients. So these are patients
who at least had three episodes over 24 hours
of non-sustain VT. At least 10 beats of over 200
beats per minute. So we're very selective. So
these were the higher risk population. That's
the only one that had a hazard ratio of two. But
all the other factors didn't play a role when
we used also LGE by itself as a factor. Force
or as a as a predictor of receiving ICD shock,
that also by itself did not. Predict or did not
increase the hazard ratio of receiving a shock.
Now, most interestingly is when we looked at the
interaction between these risk factors. So...
When we did a buy variant. Of Cox regression analysis
and looked at. Each factor, how does it interact
with LG? We found a significant synergistic interaction.
So patients who had syncope and had LGE over 10%.
At 5 times higher. The chance of receiving an
ICD shock. Fishing with an apical aneurysm. Had
around 4.6 times higher the chance of receiving
an ICD shock. As compared to people who had an
LGE less than 10%. So we found that when we add
LGE on top of already existing primary risk factors.
That's when the risk of. Sudden death. Or the
risk of ICD discharge went up. Unfortunately,
we couldn't analyze data on family history because
we didn't have a single patient with a family
history who had an LG over 10%. And septal thickness
was also difficult to analyze because most patients
with this massive LVH. Had significant amount
of LGE. So these two factors were hard to analyze
there. So the two factors that played a role in
our study were syncope plus LGE and apical pouch
plus LGE. So that's kind of, you know, to summarize
the finding of our study, that it's the interaction
between the factor and not each factor as it is.
In and of itself was a predictor of risk of sudden
death. In this population.
DR. BRYDE: Well, I think that this is a great
study and really nice of your team to point out
the fact of the association with LGE. With these
other two risk factors. With the history of syncope
and with the apical aneurysm. And of course the
guidelines, they do point out greater than or
equal to one of these risk factors, one of all
of the risk factors you have mentioned. Bye! LGE
by itself. Of course, the indicator there would
be LGE greater than or equal to 15%. So I think
it was nice that you reduced that and said, well,
maybe we don't need to say that it's 15% so as
severe on its own to qualify. For the ICD, but
let's reduce that and let's see if there's a signal.
And I think for the clinician, we can walk away
from this and say. Well, we can't ignore this.
There's still scar there, which can be a substrate
for arrhythmic potential. And when we see that
in combination with syncope and the aneurysm.
That the clinician should take note. And consider
placing the ICD. So I think that this is fantastic.
As your team continues to follow this out through
the TRi sites and continue to analyze this data.
It'll be exciting to see what associations you
find. Of course, I know we're not saying that
the the syncope alone or family history of sudden
cardiac death or massive left ventricular hypertrophy
by themselves don't warrant the ICD because you
didn't find the signal. But as you mentioned.
It just, the study wasn't powered for that. So.
So hopefully over time we'll be able to find some
more. Information with this and I think that it's
fantastic work that you are doing with your group.
Any final take-home points that we should walk
away with us?
DR. ALSIDAWI: Absolutely. I think the final take
home point is, I think the clinician, when you
see these patients in clinic, we should use...
All the factors or all the data available to us
when we make these difficult decisions. A lot
of time we hear from the patient, I have a family
history, like my father had a sudden death at
the age of, you know, let's say 55. And it was
unknown. Can I use this as a factor or not? Is
it by itself a reason to put an ICD? So adding
the imaging data on top of that. So looking at,
you know, doing an MRI, looking at their LGE data.
So. Looking at multiple factors rather than just
one factor to place an ICD is probably the right
way to go. Our guidelines currently separate them
as Class 2A and Class 2B. Probably a better way
to do it is that's what we're proposing. Can we
put these factors together and come up with a
new classification where we interact? These factors
together so we come with a better classification.
Of who's really at higher risk of sudden death
and who should read an eye. Receive an ICD.
DR. BRYDE: Perfect. Perfect. Well. Agree completely.
So you guys are definitely on the forefront and
helping us continue to risk stratify these patients.
As best we can. Thank you so much for your time
today. And we look forward to hearing from you
in the future on what your study has found as
you follow up a few years down the road.
DR. ALSIDAWI: Thank you so much for having me.
DR. BRYDE: Thank you.
ANNOUNCER: Dr. Robin Bride also had the pleasure
of speaking with Dr. Stuart Campbell, who is an
associate professor of medicine at Yale University.
His abstract presentation covers inherited cardiomyopathy
and what happens when you send a patient for genetic
testing and the panel returns back not with no
mutation, but with a gene associated with cardiomyopathy.
DR. BRYDE: Well, perfect. Well, welcome. Thank
you so much for joining in today. You again are
one of our abstract presenters at the HCMS meeting.
In Cleveland this year. And so this is an opportunity
for our listeners who are listening in virtually
to hear about your abstracts. So I will let you
take it away and give us an overview of what you
presented.
DR. CAMPBELL: Great. Thank you very much. Thanks
for having me. It's really exciting to be associated
with this meeting and to be able to share our
work. So as you mentioned, we have a longstanding
interest in inherited cardiomyopathies. And as
we've interacted with clinicians over the years,
we've become familiar with the challenge of variants
of unknown significance, right? Where you send
a patient for genetic testing, the panel comes
back not with a known mutation, but one that is
in a gene that's associated with cardiomyopathy,
but not necessarily a variant that's been seen
before. This is a challenge if you want to be
able to go on and screen the rest of the family
members and determine who might be at risk on
the basis of genetics. So if we go to clinical
databases on variants such as ClinVar, you can
see that these different variants can be classified
as known pathogenic, likely pathogenic, benign,
et cetera. And then you've got, of course, that
variant unknown significance or the US category.
So as we sort of have gone along in our research
in hypertrophic cardiomyopathy, we became interested
in seeing if we could contribute to the resolution
of some of these unknowns, see if we can turn
unknowns into knowns. And we have a variety of
different techniques that we've used that range
from computational studies, models of how these
proteins behave and how that can be translated
into predictions of physiology. In this particular
abstract, I wanted to emphasize an in vitro method
that we've been working on over the years. So
in this case, we can generate human engineered
heart tissue or EHTs from induced pluripotent
stem cells, and then we can precisely measure
the contractile behavior of those tissues. So
our hypothesis was that if we could introduce
variants of unknown significance into these tissues,
we might be able to observe contractile behavior
that could be associated with pathogenicity. We
chose in this case the gene TPM1 that encodes
cardiac tropomycin. It's obviously an important
regulatory protein in the cardiac sarcomere and
has plenty of mutations that have been positively
linked, definitively linked with hypertrophic
cardiomyopathy and also dilated cardiomyopathy.
And then we selected four variants of unknown
significance along with a couple that are associated
already with HCM and DCM to serve as kind of a
benchmark. And we engineered these variants into
a viral vector, which we could then introduce
to the human EHTs and follow changes in function.
So at the end of the day, measuring function in
these tissues that were transduced with variants
of unknown significance, we were able to observe
significant changes in the strength of contraction
and the duration of contraction that matched,
sort of lined up either with our HCM control known
mutation or our DCM known mutation and allowed
us to classify these as being similar to one or
the other. And we sort of concluded that if you
can take a variant of unknown significance and
benchmark it against one of these cases that we
might be able to draw some conclusions about the
pathogenesis of those variants.
DR. BRYDE: Yeah, I think that it's fascinating
how you have introduced, like you said, this vector
into the myocyte and then you're able to study
the hypercontractility. And I think what you...
Your results did show that one of the VUS is associated
with the TPM1 gene. Actually did result in hypercontractile
human engineered heart tissue.
DR. CAMPBELL: Yeah, that's exactly right.
DR. BRYDE: And so why did you choose the TPM1
gene?
DR. CAMPBELL: Yeah, that's a great question. This
really has its roots in our multi-scale modeling
efforts where we wanted to just begin with the
protein structure and maybe how an immune acid
substitution, a point variant might change that
structure and those dynamics and then scale that
up to physiological function. And that's obviously
very challenging to do in a computer model or
a series of models. So we decided to start with
low-hanging fruit. As you probably know, TPM1
is not a huge piece of the HCM pie, right? It's
just a few percent in terms of patients that are
coming into clinic with TPM1 mutations. However,
the structure of that protein is relatively simple.
It's arguably the simplest among the sarcomeric
proteins. And so we reasoned that this might be
a good place to start to prove the concept that
we could you know, make computational evaluations
potentially of the pathogenicity of different
variants. So we can prove that just because it's
sort of a good entry point.
DR. BRYDE: Sure, sure. And with the TPM1 gene.
Are there pathogenic variants associated with
it in addition to the variants of unknown significance?
DR. CAMPBELL: Yeah, absolutely. There's a well-established
literature in patient families for both hypertrophic
and dilated cardiomyopathy. And so that allowed
us to choose from among several sort of benchmark
mutations that we could say, this mutation has
been shown through patient data, linkage analysis
to cause hypertrophic cardiomyopathy or dilated
cardiomyopathy. And that way we could sort of
have more confidence that it would function as
a benchmark in either case.
DR. BRYDE: Sure, sure. That makes perfect sense.
So the, I think that your work is, is very fascinating
and it's exciting because. There's. Seems to be
somewhat known about how a gene is transitioned
from a VUS to a pathogenic variant. In clinic,
we oftentimes do send our patients to do the genetic
testing. And oftentimes the results come back
as a VUS and we do counsel patients that. These
are continuing to be monitored through the companies
that collect this data. When they notice an increased
signal that sometimes the US will be transitioned
over to a pathogenic variant and of course...
The office would be notified and then it would
be our role to reach out to the patient. So tell
me how do you feel like your work? Can contribute
to. Transitioning over from a view as to a pathogenic
variant, because I can definitely see that. There
could be a role for understanding this clinical
work that you're performing into. Transitioning
of the US to a pathogenic variant.
DR. CAMPBELL: Yeah, absolutely. I'm glad that
you brought this up because this is really the
core of what we want to do. We see this as where
we hopefully can make a real impact. At the same
time, we have to temper that with the need to
be cautious, the need to be really thorough in
the way that we do things. So I view this as sort
of an ongoing conversation that's got to take
place between scientists like myself, clinicians
like you, genetic testing companies. We've got
to sort of collaborate together in a consortium
type way to make steps forward. So I want to see
this move forward and to be done correctly. So
I think our role falls into two categories. First,
we have been making induced pluripotent stem cell
lines from specific cardiomyopathy patients. We've
also been using other techniques such as CRISPR-Cas9
to engineer known patient mutations into these
IPS lines and then studying the behavior of those
tissues and seeing, in fact, this pattern of hypercontractility
in our HCM patients. So we see that over and over
again. We feel that that's a pretty strong signal
and we feel like we understand a good deal of
the biology. I certainly wouldn't say all, but
a lot of the biology that underlies those responses.
And so having observed those really repeatable
physiological responses to HCM linked mutations,
We are now trying to associate that with these
variants of unknown significance and saying, look,
if this increasing contractility or this prolongation
of the contraction. Is associated with known HCM
patients, then can we build a bridge to evaluating
these unknown mutations? We'll obviously take
those results and publish them. Those will go
into the scientific literature, be peer-reviewed,
and so forth. We'll continue to generate conversations
by going to conferences. We hope that over time,
this can really challenge the field to say, is
this a functional biomarker that we believe in
that could be used for making these critical clinical
decisions or not? That's how I see our role and
how I hope it will unfold in the future.
DR. BRYDE: Absolutely. Well, it certainly is a
very exciting time and your lab is on the forefront
of this cutting edge research. And it's exciting
to see what will come with it. Of course, we'll,
like you said, track it over time. Get the data
out there. Work in collaboration with the companies
that are collecting all of the genetic data. And
we'll see what happens with this. But definitely
thank you so much for all your work in this. And...
I'm sure your lab has contributed greatly and
this is knowledge that we've. Are very grateful
for. Exciting to hear you talk about this and
look forward to seeing you in person at the meeting.
DR. CAMPBELL: Wonderful. Thank you so much. I
appreciate it.
DR. BRYDE: Absolutely. Thank you.
ANNOUNCER: Dr. Bradley Lander interviews Dr. Anjali
Owens from the University of Pennsylvania. Her
abstract presentation covers the study in patients
with symptomatic nonobstructive HCM. In the parent
study, the Maverick HCM Child. Looking at symptomatic
non-obstructive HCM patients who were treated
with either Mavacamten, a novel cardiac myosin
inhibitor versus placebo, and a long-term extension
study that's open label called NOVA-LT.
DR. LANDER: Hi, Dr. Owens, how are you?
DR. OWENS: Hi, I'm Fine Dexter Lander and thank
you so much for the invitation to speak today.
DR. LANDER: Of course. Well, congratulations on
your work. Maybe you can tell our audience a little
bit of background leading into your current study.
DR. OWENS: Absolutely, so this study is done in
patients with symptomatic non-obstructive hypertrophic
cardiomyopathy. And the parent study was the Maverick
HCM trial that was published a couple of years
ago. Looking at symptomatic non-obstructive HCM
patients. Who were treated with either Mavicamton,
a novel cardiac myosin inhibitor, versus placebo.
And this trial is the long-term extension study
that's open label. Called Mava LTE. And I will
be presenting the 120 Weeds. Long-term extension
data.
DR. LANDER: That's great. And maybe you can tell
us a little bit about what this study involved
and what you found and will be presenting.
DR. OWENS: So these were patients who were involved
in the parent study, Maverick HCM, and opted to
continue in the long-term extension. In that long-term
extension, all of the patients were treated with
Mavicamton and they were split into two groups
based on a target... Drug concentration. So there
was a low concentration. And a higher concentration.
And we watch patients in terms of how they felt.
What their New York Heart Association functional
class was. What their biomarkers were in terms
of troponin and NTPROBNP. As well as echo parameters,
looking at ejection fraction. Measures of diastolic
function, left atrial size. And of course, importantly,
we looked for safety outcomes, adverse events.
Drop in the junction fraction, which we know can
occur. With this class of medication.
DR. LANDER: And one of the interesting findings
was that the drop in ejection fraction, I believe
less than 50%, was seen in around a quarter of
the patients. Was this expected, unexpected? How
did your study team consider that finding?
DR. OWENS: I think it's an interesting finding
and one that is notable. And again, this is the
longest term. Of patients with non-obstructive
HCM. Being treated with a cardiac myosin inhibitor.
The rest of our data come from patients with obstructive
HCM. And of course, that's the Explorer study,
the Valor HCM study. And the long-term extension
of those studies. And in those populations with
obstruction... The transient drop in ejection
fraction has been observed to be much lower than
what was seen in this study. And I think there's
a couple of reasons why that might be. One is
that this study was a dose finding study. So as
I mentioned, there were two target concentrations.
And that is what the goal was, to get the drug
to that concentration. There was a higher level
and a lower level concentration. And most of the
drops in EF, about 66% of them, occurred in the
higher concentration group. As opposed to the
obstructed group where we were not targeting.
Concentration, for example, in the Valor HCM study.
But rather we were dosing the drug based on echo
findings. And in the obstructive population, importantly,
We have the biomarker of the LVOT gradient, and
we can titrate the drug. To response of the gradient
as well as EF. And I think what it tells us and
what the Maverick study told us in the long-term
extension, is how to design it, inform the design.
The Phase 3 study. Odyssey HCM. So this was very
important dose finding study. That informed how
we're going to dose the drug in the Odyssey study.
The other thing that I think is important is that
the nonobstructive population is not the same.
There are more heterogeneous populations. And
they're on a spectrum or continuum of disease.
And it's probable that the cardiac myosin inhibitors...
Aren't the best choice for all comers with non-obstructive
HCM. What we may find is that there is a subset
of patients who benefit. And maybe there's a subset
of patients who don't. And I think the phase three
trials will hopefully tell us that information.
DR. LANDER: That's fantastic. It is a really interesting
finding. And are there other trials of obstructive
HCM that are happening and how do you expect what
you're what you found currently to impact future
trials and future care patients?
DR. OWENS: Yes, so definitely it's a hot time
to be a patient with non-obstructive HCM and to
be a cardiologist who treats those patients. There
are many trials that are in development or actively
enrolling. The two big phase three randomized
controlled trials for cardiac myosin inhibitors.
The first is the Odyssey HCM trial, and as I mentioned,
that's going to be Mavicamton versus placebo.
In symptomatic non-obstructive HCM. And the next
generation cardiac myosin inhibitor, Afficamton.
Also has a phase three trial ongoing. That's the
Acacia HCM trial. That will be for symptomatic
non-obstructive HCM. In addition... We are seeing
first in human gene therapy trials. Very exciting.
For patients with symptomatic non-obstructive
HCM. And then I think down the pike, we're also
gonna see other agents like SGLT2 inhibitors,
et cetera. Being trialed in non-obstructive HCM,
as well as drugs that affect energetics, an ongoing
phase two trial. And we'll see if it turns into
a phase three. So again, there are a lot of options
now. For a patient population that traditionally
had no options. So we're hopeful that we'll find
out which drug benefits which patient. At which
time in their disease course. And I think it's
on us as cardiologists. To do that background
work now. Understand where patients are in the
phase of their disease that we know what they're
poised to benefit from.
DR. LANDER: That's a fantastic overview and I
agree completely. It's an exciting time to be
a physician in this space and it's probably the
best time so far to be a patient with the condition
if you have to have the condition. So thank you
so much for joining us and congratulations again
on your work.
DR. OWENS: Thanks again.
ANNOUNCER: Thank you to all our guests for sharing
their valuable research with us today. And thank
you to our listeners for joining us on this episode
of In the Thick of It. For more information on
this study, please click the slides in the show
notes or visit hcmsociety.org slash podcast. This
episode was edited and produced by EarFluence.
Thanks for listening and we'll talk to you soon
on In the Thick of It.