Advancements in Nonobstructive HCM: A Discussion with Dr. Michelle Kittleson

Are the symptoms of nonobstructive hypertrophic cardiomyopathy (nHCM) holding patients back from living their fullest lives? Join Dr. Melissa Lyle and Dr. Michelle Kittleson as they unravel the mysteries of nHCM symptoms like congestion, angina, and exercise intolerance. How can we better manage these symptoms and pave the way for improved quality of life?

Tune in as they explore innovative solutions, from advanced therapies to cutting-edge gene editing technologies like CRISPR, in the quest for better patient outcomes. Let's uncover the path to empowerment for nHCM patients together.

In the Thick of It is brought to you by the HCM Society, and is produced by Earfluence.

Episode Transcript

ANNOUNCER (00:05):
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 today's episode, host Dr. Melissa
Lyle interviews Michelle Kittleson, a professor
of medicine at Cedars-Sinai, director of education

(00:25):
in heart failure and transplantation, and director
of heart failure research at the Schmidt Heart
Institute. They're going to be talking about cardiomyopathy,
or NCM, and its management, with a specific focus
on symptoms such as congestion, angina, and exercise
intolerance. The discussion also extends to the

(00:45):
potential future application of gene editing technologies,
such as CRISPR, and the consideration of advanced
therapies, like cardiac transplantation, for patients
with NCM. Let's get In the Thick of It. Here's
Dr. Lyle and Dr. Kittleson.

MELISSA (01:00):
So welcome, Dr. Kittleson, and so glad
you could be with us today.

MICHELLE (01:04):
Thank you, Dr. Lyle. It's a delight
to be here.

MELISSA (01:08):
So as we know, cardiomyopathy is defined
as having no significant left ventricular outflow
tract obstruction. Or an LV outflow graft gradient
of less than 30 millimeters of mercury. Patients
with cardiomyopathy, though, can still have significant
symptoms. And treatment is relatively sparse,

(01:30):
but in their past, there was no really proven
pharmacologic therapies. For this subgroup of
patients. So, Dr. Kittleson, how do you manage
the symptoms of congestion associated with HCM
. And given the overlap between heart failure
with preserved ejection fraction, and HCM, do you think that there's a role for SGLT2 inhibitors?

MICHELLE (01:54):
Such a good question. And I have to
say the topic of this podcast is one of the most
challenging topics I deal with. You know, it's
not satisfying when a patient presents you with
symptoms of chest discomfort, dyspnea on exertion,
and you can't point to the echocardiogram and
look at an obstruction and say, aha, I know exactly

(02:14):
why you have these symptoms. Now, the symptoms
are typically from the increased left ventricular
filling pressures related to diastolic dysfunction,
function, decompensated heart failure, increased
myocardial oxygen demand, impaired microvascular
function. And assuming you've also ruled out epicardial
coronary disease, the focus on management can

(02:34):
include beta blockers or calcium channel blockers,
diuretics, if there's clear volume overload present,
but you have to be cautious to avoid symptomatic
hypotension, hypovolemia. And then you ask the
best question, can you extrapolate from current
symptoms to the best possible way to avoid symptomatic
hypotension? Currently recommended effective therapies
for garden variety heart failure with preserved

(02:56):
ejection fraction. Predominantly, we have the
strongest evidence in Heart failure with preserved ejection fraction (HFpEF) for the SGLT2 inhibitors.
I would say it's the kind of thing where it may
be useful. I categorize it in the can't hurt,
may help category. However, recognize the SGLT2
inhibitors do have a diuretic effect. And because

(03:17):
of that, if your patient gets symptomatic hypovolemia,
hypotension, kidney dysfunction, you may want
to back off. But absolutely worth a try, because
as we're realizing the multiple mysterious and
magical effects of the SGLT2 inhibitors mean they
kind of seem to work for everything.

MELISSA (03:35):
Right, absolutely. No, I definitely agree.
100% worth a try to see if it helps to relieve
some of those symptoms. And you already touched
a little bit up on it, talking about. Calcium
channel blockers and beta blockers. But when someone
is coming in mostly with the symptoms of angina
and exercise intolerance, you're focusing on beta

(03:56):
blockers and non-dihydropyridine calcium channel
blockers as first line, but Do you feel that there's
any role for Rinalazine? Or trimetazidine.

MICHELLE (04:07):
Yeah, that's really a good question.
So I'd say the first thing to remember when you
have a patient with chest discomfort and HCM,
don't assume it's always the HCM. Make sure you
have done your due diligence with history, physical,
and or other testing as guided by your history
and physical to rule out obstructive coronary
disease that would change your management. Then,

(04:28):
as you know, beta blockers and our calcium channel
blockers titrate into symptoms as limited by heart
rate and blood pressure. Okay, let's talk about
ranolazine. Studied in the HCM Trial published
back in 2018, 80 patients with symptomatic HCM randomized
placebo or ranolazine for five months. No impact

(04:51):
on exercise performance, plasma, antiprobian P,
diastolic function, quality of life. Then you
have, as you noted, trimetazidine, which is another
inhibitor. Of cardiac fatty acid oxidation. Studied
JAMA cardiology, 2019, 51 patients, symptomatic
HCM randomized placebo or trimetazidine. No impact on exercise capacity.

(05:17):
But you could say, listen, these are small studies.
Maybe they just didn't have the power to detect
the effect. So I would say the right answer is
what works. There's no reason not to try a medication
like ranolazine if nothing else is working because
the safety profile, clearance, and the ability
to detect the effect are all there. So I would say the right answer is

MELISSA (05:36):
No, I think that is fantastic advice.
And I think the two key takeaways for me is to
also make sure that we're not missing something,
as you said, not missing obstructive coronary
disease. And kind of focusing just on the hypertrophic
craniomyopathy diagnosis. But then also I like
that mantra of just what works, trying things
to help get rid of their symptoms. I think that's
great advice. So when we think now more of kind

(06:00):
of newer treatment options. So the cardiac mitotrope
Ninara Faxstat was recently evaluated in the phase
2 trial for improved HCM. And it showed improvement
in functional capacity based on CPET . Can you
explain to us how this drug works and how it could
potentially benefit patients with HCM?

MICHELLE (06:21):
So first of all, I'm really glad you
have to say the names of these medications before
I do. I mean, is it half of going to medical school?

MELISSA (06:28):
Hopefully I did say it correctly.

MICHELLE (06:30):
You did a great job. I think half of
medical school is just memorizing the pronunciation.
It's all grammar and vocabulary. So nidrofaxat,
there we go. It's a mitotrope. So what does that
mean? It's a compound which influences energetic.
So in this case, partial fatty acid oxidation.
Remember, we talked about that earlier with the

(06:51):
ranolazine, trimetazidine. So it's designed to
shift the myocardial substrate utilization in
favor of glucose oxidation to generate more ATP
per unit oxygen consumed and thereby increase
myocardial metabolic efficiency. So that's the
theory why it should be helpful in HCM. If you

(07:14):
can make energetics, myocardial energetics better,
then patients will have more efficient use of
their myocardium. Now, as you know, it's studied
in the ProveHCM. Trial, randomized, double-blind, placebo-controlled, investigating, because it was Phase 2, safety and some efficacy, nidrofaxat for 12 weeks in 67 patients with HCM HCM.

(07:36):
The top-line results came out in November of 2023
with, as you noted, a statistically significant
improvement in the functional cardiopulmonary
exercise test associated with a clinically relevant
improvement in patient health. They never want

(08:24):
to feel like, oh, it's all in my head. At least
if you have HCM, you can point at a problem. Here,
it's harder to, and thus I'm really excited by
this group of mitotropes, which may offer more
hope to our patients. So stay tuned.

MELISSA (08:40):
I think that that is a wonderful point,
too. It's because nothing has really seemed to
work. In the past. And so now we have hope. It's
sort of similar to the pathway for heart failure
with preserved ejection fraction, like we were
talking about earlier. That for so long there
was not a lot of hope. And then once we started
to get further trials with SGLT2 inhibitors, so...
I think with the cardiac mitotropes, that's offering

(09:01):
that hope, as you mentioned. For the HCM patients.
Looking forward to all of that data and potential
phase three trials in the future. And then also
pivoting to other potential drugs that might be
helpful in this realm. Of course, we know about
cardiac myosin inhibitors for HCM. So what about

(09:23):
for non-obstructive? II Phase trial demonstrated that Mavacamptin was associated with a significant dose-dependent reduction in NT-proBNP and troponin.
In patients with HCM. So Mavikampton is now being
evaluated in the phase three trial. Odyssey HCM.

(09:44):
So I feel like this is a pretty hot topic. So
Dr. Kittleson, what role do you think that cardiac
myosin inhibitors will play in treating symptoms
for HCM in the future?

MICHELLE (09:54):
This is really exciting, right? You
know, Mavacamptan is a huge game changer for patients
with HCM. And of course, HCM is not the topic of this podcast, but you will all go
and read the VALOR HCM Trial and ooh and ah about
the enormous effect size of transforming patients

(10:17):
with HCM who felt so horrible. They were willing
to undergo an invasive procedure to help their
symptoms who didn't need one anymore because this
medicine worked and improved their quality of
life to such a degree. I'm hugely impressed and
excited by the role of Mavacamptan. In patients

(10:37):
with refractory severe symptoms of HCM. But as
you know, why not repurpose it for HCM? And Maverick
took 51 patients, symptomatic HCM HCM. There was
a significant reduction in antipropion P and troponin,
suggesting improvement in myocardial wall stress,

(10:58):
but surrogate endpoints. Are not clinical endpoints.
Stands to reason it will work because regardless
of the hemodynamic features of obstructive versus
HCM, they have a shared underlying biomechanical abnormality and the sarcomeric gene

(11:18):
variants that cause HCM can destabilize the low
energy super relaxed state of cardiac myosin,
promote excessive cross bridging with actin, culminating
in hyper contractility and impaired relaxation.
So if you have a myosin , make that all go away. It stands

(11:38):
to reason that it should help if you are obstructive
or non-obstructive. But I like to say that the
road to bad outcomes is paved with plausible pathophysiology,
surrogate endpoints, and wishful thinking. We
all can think of times in cardiac history where

(12:01):
we've been burned by a thought that the improvement
in surrogate endpoints would translate into benefits.
Thiazolidine dions improved A1C, but they caused
heart failure. Hormone replacement therapy makes
your lipid profile look better, but oops, on the
whole, it's not that great for you long term.
Oh, and what about flecainide? Make your PVCs

(12:21):
go away post-MI, but you might actually die sooner.
So all of that to say, I'm very excited. I'm cautiously
optimistic, but show me the data before we know
what's going to help our patients.

MELISSA (12:34):
I love that. And I think, you know, key
takeaway is that surrogate endpoints, like you
mentioned, not clinical endpoints. So. Let's see
the data and be hopeful, but definitely want to
see the data for sure. So thank you for that.
That was great. Now, we think about kind of the
hotter topics that everyone's talking about. You

(12:56):
know, obviously in the amyloid world, we talk
a lot about... CRISPR. And so What do you think
about gene editing for patients with cardiomyopathy?
Do you think that there will be a role for gene
editing in the future?

MICHELLE (13:10):
I mean, it's a brave new world, isn't
it? It's so important to be a doctor. You know,
when I was in medical school, I was like, stop
with all the new information. I can't even memorize
the old information. But once you've been doing
it for a while, it's so exciting that there's
new things to delve into to try to understand
to help our patients. So there are two studies
that came out in Nature Medicine in 2023, using

(13:33):
this CRISPR-Cas9 . They took mice models of HCM,
and they had a common pathogenic variant, the
MYH7 mutation, and they showed dramatic reduction
in hypertrophy and fibrosis by using this fancy

(13:54):
gene editing technology. So both studies showed
an improvement. In the disease phenotype, better
contractility, reduced fibrosis on histology.

MELISSA (14:04):
But I mean, mice aren't humans.

MICHELLE (14:07):
It's like all the pediatricians say,
children are not little adults. OK, I'll say mice
are not humans. So super exciting. I mean, exciting
enough to be presented in Nature Medicine. But
wow. I mean, if we redo this podcast in five years,
when we're older and wiser, probably have more
to say.

MELISSA (14:27):
Absolutely. So not quite ready for prime
time, but... The future to be determined. So we've
talked a lot about kind of the basics with beta
blockers. And non-dihydropyridine calcium channel
blockers. We've talked about more experimental
treatment with cardiac mitotropes and also the
potential for cardiac myosin inhibitors. But what

(14:50):
happens when all of those therapies don't work?
And a patient comes with more advanced symptoms
that are life-limiting, and we need to start thinking
about advanced therapies such as cardiac transplant.
So when do you start thinking about that and how's
your initial evaluation for those patients?

MICHELLE (15:09):
Perfect. So whenever I evaluate any
patient for heart transplantation, advanced therapies
in general, or hypertrophic cardiomyopathy in
particular, I ask myself two questions. Is their
heart sick enough? And is the rest of their body
well enough? So is their heart sick enough, particularly
in patients with HCM? Your very first question

(15:31):
is going to be, do they have have obstructive
physiology? Because if they do, well, focus on
that. Give them the beta blocker, calcium channel
blocker, disopyramin, mavicamtin. Give them a
septal reduction therapy, alcohol, septal ablation,
surgical myectomy, because you can try to fix
that short of a transplant. But if you have convinced

(15:51):
yourself it is truly HCM, then you can say the next
step, how do you figure out if the heart is sick
enough? It would be the traditional criteria we
use. For really any other patient, did they have
progressive symptoms, inability to do their daily
activities without shortness of breath? Are they

(16:12):
getting hospitalized because of decompensated
heart failure? Are they having intractable and
scary and life-threatening ventricular arrhythmias?
Are they developing end organ dysfunction related
to their cardiomyopathy with cardiorenal syndrome,
worsening liver function, rising pulmonary artery
pressures? And when you start to rack up those

(16:32):
findings is when you, when you start to worry.
It can be useful to have objective criteria from
a right heart catheterization and a cardiopulmonary
exercise stress test documenting reduced functional
capacity. And a few pearls to remember. When we
think about HCM, these patients are typically
hyperdynamic and bad things start to happen when

(16:53):
their EF falls below 50%. So red flag warning
for an EF of less than 50%, not like your traditional
HEF-REF. You start thinking about bad systolic
disease. And when you start to worry, you start
to worry, you start to worry, you start to worry,

(17:34):
think, is the heart sick enough? Make sure you've
ruled out HCM. And have you looked at the traditional
criteria of why patients are limited? And then
is the rest of the body well enough? And likely
they will be because they don't have the typical
comorbidities due to their relatively young age.

MELISSA (17:51):
Perfect. That is excellent and really
wonderful pearls there. So we have covered a lot
today, really the whole spectrum of treatment
options for cardiomyopathy . Dr. Kittleson, thank
you so much for joining and for all of the wonderful
pearls. And thank you to everyone for listening

(18:11):
In to this episode of In the Thick of It.

MICHELLE (18:14):
Thank you. It was a pleasure to be here.

ANNOUNCER (18:21):
That was Dr. Lyle and Dr. Kittleson.
For more information on HCMA, visit www.hccm.org.
This episode was edited and produced by Earfluence.
Thanks for listening, and we'll talk to you soon
on In the Thick of It.