October 18, 2023 • 29 mins
Our topic of discussion today is a critical one that impacts the world of cardiology and beyond cardiac myosin inhibitors. This cutting-edge area of research has the potential to revolutionize the way we approach cardiac diseases, and our experts are here to shed light on the latest developments, breakthroughs, and implications for patients and athletes alike.
So, whether you're a medical professional, a sports enthusiast, or simply someone interested in the intersection of sports and cardiology, you're in for a treat! Dr. Michael Ayers and Dr. Anjali Owens are here to share their insights, expertise, and passion for this groundbreaking field.
About our Host and Guest:
Dr. Michael Ayers is a sports cardiologist caring for hypertrophic cardiomyopathy patients, a genetic condition causing the thickening of the heart muscle.
Dr. Anjali Owens is a Medical Director, at the Center for Inherited Cardiac Disease and Associate Professor of Medicine (Cardiovascular Medicine) at the Hospital of the University of Pennsylvania
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
ANNOUNCER (00:05):
You're listening to In the Think 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, sports cardiologist
Dr. Michael Ayers has the pleasure of speaking
with Dr. Anjali Owens, medical director at the
(00:25):
Center for Inherited Cardiac Disease and associate
professor of cardiovascular medicine at the Hospital
of the University of Pennsylvania. The topic of
discussion today is a critical one that impacts
the world of cardiology and beyond, cardiac myosin
inhibitors. This cutting edge area of research
has the potential to revolutionize the way we
(00:45):
approach cardiac diseases. So whether you're a
medical professional, a sports enthusiast, or
simply someone interested in the intersection
of sports and cardiology, you're in for a treat.
Dr. Ayers and Dr. Owens are here to share their
insights, expertise, and passion for this groundbreaking
field. Let's get in the thick of it. Here's Dr.
Ayers and Dr. Owens.
DR. AYERS (01:06):
We always learn so much chatting with
you, so we're really excited to. Ask some questions.
With that, I'm just gonna hop right in. Sounds
good. Help us understand. What patients might
benefit from a cardiac myosin inhibitor?
DR. OWENS (01:21):
Well, typically in our clinic, we've
been following the data that's been published
on Mavichamton, the FDA approved cardiac myosin
inhibitor. And that's the data from the Pivotal
Explorer trial that enroll patients with symptomatic
obstructive HCM. New York Heart Association class
two and three. The vast majority of those patients,
(01:43):
as you know, were functional class two. And then
we also use data from the Valor HCM trial, another
phase three trial of Mavichempton, which looked
at the sicker group of patients, those who were
actively considering and eligible for septal reduction
therapy. The vast majority of those patients as
you know. Or NYHA functional classes. Three. So
(02:06):
as we extrapolate this data into the real world,
those are really the patient population that we're
targeting. In our clinic, symptomatic, obstructive
HCM. Patients who are already on background therapies
at maximally tolerated doses.
DR. AYERS (02:22):
Excellent. So many of these patients
have been living with their symptoms for so long,
there can be a tendency to potentially underplay
how symptomatic they are. You mentioned that the
two things you're looking at is New York Heart
Association class. And gradient. What do you do
when there's a dissociation between those two
worlds when you got a patient with a lot of gradient
(02:43):
who's saying, I'm doing pretty well?
DR. OWENS (02:45):
Yeah, it's a wonderful question and
you know an issue that we run into all the time
with our patients with HCM. We do a couple of
things. One is during the patient's interview
every time they come to clinic. We get corroborating
history. From their significant other or caregiver
or anyone that accompanies them to clinic. And
(03:06):
as you know, oftentimes the patient is saying,
I'm fine, I'm fine. And the spouse in the background
is saying, no, they're not. So we always get information
from the caregiver or the spouse to say, how is
this patient doing really? And how does this compare
to their functional status a year ago or even
two years ago or five years ago? Have they lost
(03:27):
some functional capacity or exercise tolerance
over the years? The second thing that we use very
frequently... Is objective functional testing,
so exercise stress echo. So look at their exercise
time, look at their exercise capacity objectively.
And we do that over time. So we would do an exercise
(03:48):
stress echo every couple of years, certainly more
frequently if there's been a reported change in
symptoms. But even in someone who's got severe
obstruction but is reporting no major symptoms,
we would get that additional objective exercise
testing. And that sometimes helps us to really
eliminate that discrepancy. If it comes up.
DR. AYERS (04:10):
If you had to ballpark for me, what
percent of your patients in your HCM clinic do
you think have had a stress echo at some point
in their care with you?
DR. OWENS (04:18):
At some point in their care. 99%. I
would say it's rare that we don't try to put a
patient on a treadmill. Most of them get some
sort of exercise test at some point in their evaluation,
whether it's a baseline or a follow up. But usually
patients get some form of exercise testing. We
use the, you know. Um. Regular old stress echo
(04:42):
for most patients. There is a subset of patients
who also get a cardiopulmonary exercise test or
a peak VO2. And in some patients we do a combination
study. A stress echo CPAT.
DR. AYERS (04:58):
So you've now identified a patient
that you think might benefit from a cardiac myosin
inhibitor. Can you talk about two things for me?
One. Do you offer multiple therapies at once for
that patient who's quote unquote failing negative
inotropic therapy? And two, once they've decided
on cardiac myosin inhibitor, can you walk me through
(05:18):
the steps of what that looks like for the patient
in your clinic?
DR. OWENS (05:22):
Yeah, sure, Mike. So first we start
by giving them all the options. We really do set
aside time. To have an in-depth shared decision-making
conversation. And during that conversation, we
offer them all of the options that we think would
be. Realistic or potentially feasible for them.
And that would include going up on their avianotal
(05:43):
blocker dose if there's still room to titrate.
That might include a discussion of disopuramide,
depending on availability. You know, comorbidities.
Profile that we anticipate. For side effects,
for example, if they have prostate disease or
something else. And we talk about septal reduction
therapy in those patients who are symptomatic
(06:04):
enough to consider. So we go through all of those
options in addition to the option of cardiac myosin
inhibitor. If they decide that they're going to
move forward with the cardiac myosin inhibitor,
then we really start to talk about logistics.
And in that first visit, prior to signing them
up, prior to doing the Rams. We really talk about
(06:27):
what cardiac myosin inhibitor therapy entails.
In terms of follow-up, in terms of reporting of
symptoms, in terms of reporting concomitant and
new medications. So, we really go in depth with
why the FDA has required a REMS program and what
their responsibility will be, as well as what
(06:48):
our responsibility will be. And we make sure that
that's really a feasible approach for them, that
they can come back for those six to seven echoes
in the first year. That they have transportation
to do so. That they're able to communicate with
their primary care physician to let them know
about this new medication. We really go through
each step of the process.
DR. AYERS (07:09):
You had me smile a little bit there
when you said disapyramide. I'm sure you don't
remember this, but the very first patient I took
care of as an intern in the cardiology unit was
a patient of yours who was a new start of disapyramide.
I still remember that day.
DR. OWENS (07:24):
Oh my.
DR. AYERS (07:25):
Not so you know.
DR. OWENS (07:26):
Those were the days.
DR. AYERS (07:30):
All right, so I'm a patient who's decided
to start cardiac myosin inhibitor even after our
conversation. As my gradient improves through
time, what things are you looking for on the Echo
beside the gradient and how are you managing my
other medications like my beta blocker and my
calcium channel blocker that might have been at
(07:50):
relatively high doses before initiating this myth?
DR. OWENS (07:53):
Yeah, it's a wonderful question and
an area where I think we'll get more data in the
coming years and we'll understand kind of what
the pathways are for managing background therapy.
Currently, I think it's more of an art than a
science. So I'll give you my approach, but I think
you'll find lots of variability. Between cardiologists.
Typically what we do for my patients is they're
(08:14):
on high dose calcium channel blocker, high doses
of verapamil or diltiozum. I generally reduce
the dose of calcium blocker. Just prior to starting
the Mavicampton. So, you know, when we're in that
phase of getting approval, prior authorization,
arranging for shipping in those couple of weeks.
I may reduce the dose of counting blocker, see
(08:37):
how they tolerate it, and if they're fine on that
lower dose, go ahead and start the Mavic Hampton.
For patients on metoprolol, I generally leave
them at the dose. Sometimes I opt to reduce the
dose a bit. Then I wait for usually 12 weeks until
they reach a steady state. We've got the gradient
under control. The other things we look for, of
(08:58):
course, are the ejection fraction. The degree
of Tham, mitral regurgitation, diastolic function.
Make sure that things are all moving in the right
direction, and importantly, that the patient is
feeling better. And their symptoms are controlled.
At that point. We may need some adjustment in
blood pressure medication. We have seen patients.
(09:20):
As the LVOT obstruction is relieved that they
become hypertensive or more hypertensive. So we
may be doing some. Adjustment of their anti-hypertensive
therapy if they have hypertension. So we generally
try to do one thing at a time. And inevitably
they come to us and say, when can I get off of
my beta blocker and or calcium blocker, but more
(09:40):
often the beta blocker due to limiting side effects,
as you know. And so then we started slowly down
to high trait again, as long as the symptoms are
improved. The gradient is gone, they're at a steady
state, then we would slowly reduce the background
therapy. That's been our approach. How about you?
DR. AYERS (09:57):
Well, in full confession, given that
most of my learning about HCM came from you and
Dr. Day, I do something very similarly. You won't
be. You won't be surprised to hear.
DR. OWENS (10:06):
Excellent.
DR. AYERS (10:09):
I not a day goes by an HCM clinic when
I don't ask myself what would Anjali do. So just
so you know, again. So you mentioned following
the ejection fraction for these patients. One
of the things that's sort of cognitively difficult
for these patients is They'll feel so much better
with alleviation of gradient, but I'm sure you've
(10:31):
had a handful of patients that start to really
skirt into an ejection fraction of the high 40s,
low 50s. What are you doing for your patient who's
got an EF? We'll just make it right at 49. But
the gradients gone and they feel great. And how
are you having that conversation with the patient
about the meaning or... Absence of meaning about
(10:52):
systolic dysfunction in those instances.
DR. OWENS (10:55):
Great, wonderful question. So as you
know from the trial data, many patients with the
transient drop in ejection fraction to less than
50% on a CMI, many of them are asymptomatic. Just
as you said, it's picked up by that safety echo,
but they're feeling otherwise fine. Their gradient
is gone. So they do have a hard time wrapping
their head around the concept at times. Just as
(11:17):
they have. Difficulty wrapping their head around
the concept of down titration of dose at week
four. Or weak aid. When they're feeling very well
and the gradient is gone. So it's a similar conversation
that we have. And I think a lot of it is really
predicated on the original discussion that you
have with the patient. As you're signing them
(11:38):
up for the REMS protocol and to use Mavic Hampton.
And it's during that initial conversation. Where
we say this is a novel mechanism of action. Here's
how the drug works. And as a result of that, you
may reach a stage where you're... Hypo-contractile.
And we are going to temporarily stop. And then
(11:58):
restarted a lower dose should that occur. And
so I think. Setting expectations so that patients
are not disappointed and it doesn't seem like
it's coming out of the blue is important. And
so that's what I say, we've reached that point
where your ejection fraction's a little bit low,
it's not causing you heart failure, you're feeling
well otherwise, we are gonna temporarily hold.
(12:19):
And then restart after a follow-up echo shows.
Recovery of the ejection fraction to above 50.
Now we do have many patients. Who are living in
that kind of low to mid 50 range and they feel
very well. And we're not doing anything for them.
We're continuing their dose of Mavicamptan. But
if they drop transiently below, then we are temporarily
(12:40):
holding. As you know, this often happens in the
setting of paracysmal AFib. So we're very careful
to tell our patients when they're starting Mavicamptan,
we wanna know if you go into AFib. Don't sit at
home for weeks in the AFib and not let anybody
know. Call us and tell us. And will make moves
to get you back into sinus rhythm if the paroxysm
hasn't gone away on its own. And that puts them
(13:02):
at less risk, I think, to drop the EF in that
setting.
DR. AYERS (13:06):
And ballpark, how many patients have
you seen at this point as a percentile maybe who
have dropped their ejection fraction and required
either cessation of the drug entirely or a pause.
DR. OWENS (13:16):
Very few. So I've seen more in our
clinical trial population because we've been following
those patients for now four plus years. From the
Explorer cohort. And from the long-term extension
of the Valor trial. We've seen a couple of, you
know, a handful of patients from the clinical
trial setting. In our commercial population that
(13:38):
has been started on Mavic Hempstead since FDA
approval. It's been about two patients. And that's
out of... Close to 90 or 100. So it's below 5%,
probably around 2% if I had to guess. How about
you?
DR. AYERS (13:55):
We've got about 40 to 50 people on
drug right now at the ballpark and we had two
drops. One within the setting of a hospitalization
for heart failure. That was actually related to
the tricuspid valve going wonky, nothing to do
with the HCM. And the second one was, as you nailed,
patient who had some breakthrough of atrial fibrillation
(14:16):
and dropped the ejection fraction in that setting,
and is requiring some more aggressive care with
our electrophysiology team to try and manage that.
DR. OWENS (14:25):
Yeah, I think that's been pretty typical.
We of course always warn patients that a serious
intercurrent illness that's non-cardiac. May also
be a time where they may be particularly vulnerable.
And again, this is based off of what we've seen
in some of the clinical trial populations. So
we do warn the patients if you have a serious
infection, any other serious medical illness that
(14:47):
they should let us know so we can be vigilant
about potentially. Monitoring the EFR closely
or temporarily holding drug if we need to.
DR. AYERS (14:55):
Do you think there will be a role not
to get too far off the beaten path? For a reversal
agent at some point in patients as we get more
and more patients on drugs.
DR. OWENS (15:06):
Interesting concept. I think, you know,
at least in the preclinical studies that the effect
of the cardiac myosin inhibitors could be overcome
by inotropes for the most part. And so I think
if you really have someone who gets into trouble
and is clinically in shock, cardiogenic shock,
something like that, then you can probably use
inotropes to get over a lot of the effect. If
(15:29):
it's a case like a massive overdose of a CMI,
then the CMI is a massive overdose. Perhaps there
would be a role for a reversal agent. God forbid,
hopefully that doesn't happen, but it's always
a possibility. Um. So I'm not sure if we'll need
a reversal agent. What are your thoughts on that?
DR. AYERS (15:48):
There's some case reports coming out
of Boston, I believe, about a patient, Perry Transplant,
who had stopped meds pretty well before their
transplant and then had kind of an abrupt drop
in ejection fraction post-transplant that was
maybe related. Maybe not, we know how rocky it
can be coming out of transplant. I think they
did get a compassionate use in that instance,
(16:10):
I don't know all the details of the case. But
it certainly made me think as we get more and
more patients on drugs. What happens when they
come in with say a run-of-the-mill heart attack?
Are we going to need some way to reverse this
medication? And so I was selfishly using this
time to pick your brain about where the future
of that was.
DR. OWENS (16:29):
No, certainly transplant is a tough
one and I would. Wrongly suggest that anyone being
listed for transplant is taken off of a cardiac
myosin inhibitor. I think that those two do not
mix well. So certainly that would be the case.
You know, someone with a big acute myocardial
infarction, harder to know what we'll do in that
(16:50):
setting. I mean, certainly that will. Probably
occur with enough people on these drugs, then
we'll have to know if finotropes are. Temporary
MCS is enough. I think down the pike in preclinical
studies and certainly with next generation. CMIs
with a shorter half life like Afikampton that
could be a potential benefit for getting off of
(17:10):
the drug quickly if you need to that the half
life is a bit shorter. There may be other alternatives
that may come up. That would help with that issue.
DR. AYERS (17:20):
Similar to the drop an ejection fraction.
Another way that you can kind of fail to use that
word loosely a cardiac myosin inhibitor is to
have an ongoing gradient despite their How often
are you seeing that and are there any features
that in your mind predict that might happen? Maybe
it's elongation of the anterior leaflet, more
(17:41):
of a mid-cavatary gradient. Is there anything
you're seeing that's not really happening? Gives
you a clue. That this patient might not fly on
just cardiac myosin.
DR. OWENS (17:50):
Yeah, what I've seen so far is mainly
anatomy just as you alluded to. Very long abnormal
mitral valves where it's more than just hyperdynamic
LV function that's contributing to the LVOT obstruction.
And there's really a mechanical anatomic reason.
(18:10):
Those patients may not respond as well, at least
the few that we've seen. They are options, of
course, for surgery. And may opt to do so if they
don't feel better and their gradient is still
present. We have seen in a couple of those patients
that despite still having obstruction, in the
severe range by gradients that they feel better.
(18:32):
And their NT-proBMP has come down. And so in a
couple of those patients, they have opted to consider,
continue the CMI and not pursue surgery. But I
think patients should know that if their obstruction
is still present, still severe, and they still
have symptoms, that they really should be pivoted
over to surgery if their gradient isn't resolving.
(18:53):
The second group of patients, and again, it's
small, but a bit notable. Are our very large mess.
And I wonder if that may be due to dosing and
kind of upper limits of dosing. It's anecdotal
and it's a couple of patients, but they tend to
be large men. And so I wonder if there may be
(19:13):
an effect there. Hopefully we'll get more data
as the drug is expanded to more real world populations
where. BMI may be higher, comorbidities may exist
that may affect the efficacy of the drug.
DR. AYERS (19:27):
That's very interesting you say that.
We have one or two that still have significant
residual gradient. And I had unified them in my
head as mitral anomalies, as you had said, both
of them very long anterior leaflets, a little
bit of apical displacement. More than what you're
used to seeing. But now that you say that, they
both are. Higher BMI men, so it raises the question
(19:49):
do they need to be? A bigger dose. Very interesting.
DR. OWENS (19:52):
Yeah, and I think, you know, certainly
within the FDA requirements now this early after
approval. I am not suggesting in any way that
we go above the recommended dosing limits. But
as time goes on and we get more experience you
know perhaps there would be a role for doing off-label
treatment. But at this point I would say no. You
know stick with what the FDA has done. Approved
(20:13):
and for safety reasons to do that. There's also
the metabolizer status that may play a role. So,
you know, if you have a fast metabolizer who happens
to also have a BMI, like perhaps there's a small
segment of people that that's just not the right
dose for them. We're not checking PK values, as
you know, that's not mandated by the FDA. And
(20:34):
so. And some of those real world patients, we
just don't know what their drug concentration
is and what their drug exposure is.
DR. AYERS (20:43):
There have been some whispers that
I've heard about increased rates of atrial fibrillation
in this population after starting med. Do you
think there's any truth to that? Have you experienced
that? Do you think we just need more data at this
point? How are you viewing that situation?
DR. OWENS (21:00):
I think the jury's out. I'm not sure
what's going to happen with the AFib data and
the paroxysms of AFib in particular. I certainly
think we need more data with that regard, longer
term data and good reporting. Oftentimes patients
will have a paroxysm of AFib and not really mention
it, not really think it's that big a deal as long
(21:22):
as it resolves. But that is data that may be harder
to capture. Hopefully the Discover registry or
real world registries will be able to get some
of that information. We're of course instructing
our patients to let us know if they have more
AFib. But I'm not certain, you know, and then
when you look at the longer term data, for example,
(21:44):
the MRI and echo studies, We're. Certainly seeing
an improvement in left atrial volume index. One
would think that that would lead perhaps to decrease.
I think it's something to take note of and certainly
something to follow in the patients that have
it to see if a trigger or some other interaction
(22:07):
can be identified.
DR. AYERS (22:10):
All right. I have three crystal balls
questions to end here. We'll see how much you're
willing to bite off. Oh boy. My first question
is... Is this a disease modifying agent? Should
we as cardiologists be calling this a DMARD at
this point or not enough data?
DR. OWENS (22:28):
I think we need a bit more data. So
it's tantalizing to bite on that one. And say
it's disease modifying. But as you know, I trained
as a heart failure physician and so I really would
like to see some. Longer term. Outcomes data.
This is of course hard to get in an HCM population,
but I do think we need a bit more data before
(22:52):
we're willing to say this is a test. Modifying
drug. I think the Remodeling is notable. And it
certainly gives us. Pause to say that hopefully
this will be a disease modifying drug. But I don't
think I would say that just yet. The other thing
that's in my mind is I don't know whether or not
(23:15):
patients will need the same dose of CMI long term.
That they need up. Particularly in the obstructed
population. To get resolution of obstruction.
After that point, when patients are on four or
five years. I don't know if maybe perhaps we need
to reduce the dose to more of a maintenance dose.
(23:35):
We certainly need more data with regard to what
to do with these drugs longer term. We'll get
a lot of good data from the ongoing phase three
trials in non-obstructive HCM. That might inform
us more about what the long-term effects of the
drug are going to be in that population. So, I
would still stop short of calling them disease
modifying. I would say potentially disease modifying.
DR. AYERS (23:59):
Yeah, it's very exciting to think about
some of the new opportunities for our patients
that have been opened up. Say a patient with suboptimal
coronary anatomy for alcohol ablation. Getting
up. Pretty good response from CMI and maybe now
you think about two therapies at once, right,
rather than a this or that. A little bit above.
(24:21):
You see. A number of different scenarios where
you might have multiple therapies being utilized
for our patients.
DR. OWENS (24:28):
Most definitely. And I think another
population where, you know, dual SRT followed
by CMI might be beneficial are the patients who
have, you know, very severe symptomatic obstruction.
They undergo adequate. Septal myectomy. But then
end up with. Diastolic heart failure. And a very
(24:49):
stiff and thick ventricle that has normal systolic
function, but nonetheless their NT Pro is still
elevated, they still have severe symptoms. That's
another population that I think the CMIs may be
very useful. As you know, they affect all of the
myocardium. So, you know, not just the part that
was cut out by the surgeon, but the whole myocardium
is being affected by the drug. And I think those
(25:11):
patients may benefit. Significantly. We'll get
more data of course from audits and indications.
For that population.
DR. AYERS (25:18):
You read into my crystal ball before
I even got to the question and that is, what are
you looking for in the non-obstructive trial and
what do you think might happen? I know you're
partially handcuffed. Both as a PI and as a...
Heart failure physician who loves her data, but...
What do you think we're gonna see?
DR. OWENS (25:35):
Yeah, I think what we'll see is that.
Non-obstructive HCM is much more heterogeneous
than obstructive HCM. So I think that we need
better phenotyping. To allow for subgroups of
non-obstructive HCM that we understand more deeply
than we currently do. And there are some patients
(25:55):
with non-obstructive HCM who have accumulated
significant fibrosis, their ejection fraction
is already on the low end, they have more congestive
symptoms. And maybe even borderline cardiac output.
And as you know, with band of the right heart
cath, so I think we can get hemodynamic data to
help us. And those patients may benefit more from
(26:19):
SGLT2 inhibitor and more going towards the HFREF
route. Of medical therapy. Whereas other patients
with non-obstructive HCM still have quite a hyperdynamic
LVEF in the mid 70s. You know, big life left atria.
High filling pressures. And those patients I think
(26:40):
will benefit from the cardiac myosin inhibitors.
But I think it's a lot more difficult to pick
out. Who's going to benefit with non-obstructive
HCM. The other thing we have to consider in that
population is the high rate of comorbidities in
some of those patients. Including obesity and
other medical comorbidities that may affect their
(27:02):
response and the efficacy of CMIs. And we see
that a little bit in our obstructive population
in the real world now that we are treating patients
with higher BMIs or. Other medical issues that
may affect their exercise tolerance. And I think.
That will be amplified in the non-obstructive
population. So I think we have to be careful.
Particularly with enrolling for the clinical trials.
(27:24):
To see which populations may benefit.
DR. AYERS (27:29):
All right. Last question, I could do
this all day with you. I hope you know the clarity
of your explanation lives in my head, relatively
rent free all the time in clinic. But I will ask
just one more question of you and that is. Between
cardiac myosin inhibitors, afficamton, possibly
bringing more competition to the market, the non-obstructive
(27:49):
trial coming down the pipeline, more and more
patients feeling better, the genetic. Trials that
are rolling out. What are you most excited about?
In the HCM sphere right now.
DR. OWENS (28:02):
Well, that's a tough one. That is a
tough one. Um Well, you know, one thing you didn't
mention, there are some agents in preclinical
evaluations that will be hopefully coming to.
Phase one first in human. That actually have more
of a lucidropic. And less effect on systolic function.
(28:24):
And I'll leave that as a cliffhanger. But I'm
pretty excited about hearing more about those.
DR. AYERS (28:30):
Alright. Excellent answer. Thank you
for answering all my texts about patience when
I need it and thank you for all the training and
for your time I really love talking to you
DR. OWENS (28:39):
You're very welcome, Mike. You're too
sweet. Thanks again.
ANNOUNCER (28:47):
That was Dr. Michael Ayers and Dr.
Anjali Owens. For more information on HCMA, visit
4HCM.org. That's number 4HCM.org. This episode
was edited and produced by Ear Fluence. Thanks
for listening and we'll talk to you soon on In
the Thick of It.
You're listening to In the Think 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, sports cardiologist
Dr. Michael Ayers has the pleasure of speaking
with Dr. Anjali Owens, medical director at the
(00:25):
Center for Inherited Cardiac Disease and associate
professor of cardiovascular medicine at the Hospital
of the University of Pennsylvania. The topic of
discussion today is a critical one that impacts
the world of cardiology and beyond, cardiac myosin
inhibitors. This cutting edge area of research
has the potential to revolutionize the way we
(00:45):
approach cardiac diseases. So whether you're a
medical professional, a sports enthusiast, or
simply someone interested in the intersection
of sports and cardiology, you're in for a treat.
Dr. Ayers and Dr. Owens are here to share their
insights, expertise, and passion for this groundbreaking
field. Let's get in the thick of it. Here's Dr.
Ayers and Dr. Owens.
DR. AYERS (01:06):
We always learn so much chatting with
you, so we're really excited to. Ask some questions.
With that, I'm just gonna hop right in. Sounds
good. Help us understand. What patients might
benefit from a cardiac myosin inhibitor?
DR. OWENS (01:21):
Well, typically in our clinic, we've
been following the data that's been published
on Mavichamton, the FDA approved cardiac myosin
inhibitor. And that's the data from the Pivotal
Explorer trial that enroll patients with symptomatic
obstructive HCM. New York Heart Association class
two and three. The vast majority of those patients,
(01:43):
as you know, were functional class two. And then
we also use data from the Valor HCM trial, another
phase three trial of Mavichempton, which looked
at the sicker group of patients, those who were
actively considering and eligible for septal reduction
therapy. The vast majority of those patients as
you know. Or NYHA functional classes. Three. So
(02:06):
as we extrapolate this data into the real world,
those are really the patient population that we're
targeting. In our clinic, symptomatic, obstructive
HCM. Patients who are already on background therapies
at maximally tolerated doses.
DR. AYERS (02:22):
Excellent. So many of these patients
have been living with their symptoms for so long,
there can be a tendency to potentially underplay
how symptomatic they are. You mentioned that the
two things you're looking at is New York Heart
Association class. And gradient. What do you do
when there's a dissociation between those two
worlds when you got a patient with a lot of gradient
(02:43):
who's saying, I'm doing pretty well?
DR. OWENS (02:45):
Yeah, it's a wonderful question and
you know an issue that we run into all the time
with our patients with HCM. We do a couple of
things. One is during the patient's interview
every time they come to clinic. We get corroborating
history. From their significant other or caregiver
or anyone that accompanies them to clinic. And
(03:06):
as you know, oftentimes the patient is saying,
I'm fine, I'm fine. And the spouse in the background
is saying, no, they're not. So we always get information
from the caregiver or the spouse to say, how is
this patient doing really? And how does this compare
to their functional status a year ago or even
two years ago or five years ago? Have they lost
(03:27):
some functional capacity or exercise tolerance
over the years? The second thing that we use very
frequently... Is objective functional testing,
so exercise stress echo. So look at their exercise
time, look at their exercise capacity objectively.
And we do that over time. So we would do an exercise
(03:48):
stress echo every couple of years, certainly more
frequently if there's been a reported change in
symptoms. But even in someone who's got severe
obstruction but is reporting no major symptoms,
we would get that additional objective exercise
testing. And that sometimes helps us to really
eliminate that discrepancy. If it comes up.
DR. AYERS (04:10):
If you had to ballpark for me, what
percent of your patients in your HCM clinic do
you think have had a stress echo at some point
in their care with you?
DR. OWENS (04:18):
At some point in their care. 99%. I
would say it's rare that we don't try to put a
patient on a treadmill. Most of them get some
sort of exercise test at some point in their evaluation,
whether it's a baseline or a follow up. But usually
patients get some form of exercise testing. We
use the, you know. Um. Regular old stress echo
(04:42):
for most patients. There is a subset of patients
who also get a cardiopulmonary exercise test or
a peak VO2. And in some patients we do a combination
study. A stress echo CPAT.
DR. AYERS (04:58):
So you've now identified a patient
that you think might benefit from a cardiac myosin
inhibitor. Can you talk about two things for me?
One. Do you offer multiple therapies at once for
that patient who's quote unquote failing negative
inotropic therapy? And two, once they've decided
on cardiac myosin inhibitor, can you walk me through
(05:18):
the steps of what that looks like for the patient
in your clinic?
DR. OWENS (05:22):
Yeah, sure, Mike. So first we start
by giving them all the options. We really do set
aside time. To have an in-depth shared decision-making
conversation. And during that conversation, we
offer them all of the options that we think would
be. Realistic or potentially feasible for them.
And that would include going up on their avianotal
(05:43):
blocker dose if there's still room to titrate.
That might include a discussion of disopuramide,
depending on availability. You know, comorbidities.
Profile that we anticipate. For side effects,
for example, if they have prostate disease or
something else. And we talk about septal reduction
therapy in those patients who are symptomatic
(06:04):
enough to consider. So we go through all of those
options in addition to the option of cardiac myosin
inhibitor. If they decide that they're going to
move forward with the cardiac myosin inhibitor,
then we really start to talk about logistics.
And in that first visit, prior to signing them
up, prior to doing the Rams. We really talk about
(06:27):
what cardiac myosin inhibitor therapy entails.
In terms of follow-up, in terms of reporting of
symptoms, in terms of reporting concomitant and
new medications. So, we really go in depth with
why the FDA has required a REMS program and what
their responsibility will be, as well as what
(06:48):
our responsibility will be. And we make sure that
that's really a feasible approach for them, that
they can come back for those six to seven echoes
in the first year. That they have transportation
to do so. That they're able to communicate with
their primary care physician to let them know
about this new medication. We really go through
each step of the process.
DR. AYERS (07:09):
You had me smile a little bit there
when you said disapyramide. I'm sure you don't
remember this, but the very first patient I took
care of as an intern in the cardiology unit was
a patient of yours who was a new start of disapyramide.
I still remember that day.
DR. OWENS (07:24):
Oh my.
DR. AYERS (07:25):
Not so you know.
DR. OWENS (07:26):
Those were the days.
DR. AYERS (07:30):
All right, so I'm a patient who's decided
to start cardiac myosin inhibitor even after our
conversation. As my gradient improves through
time, what things are you looking for on the Echo
beside the gradient and how are you managing my
other medications like my beta blocker and my
calcium channel blocker that might have been at
(07:50):
relatively high doses before initiating this myth?
DR. OWENS (07:53):
Yeah, it's a wonderful question and
an area where I think we'll get more data in the
coming years and we'll understand kind of what
the pathways are for managing background therapy.
Currently, I think it's more of an art than a
science. So I'll give you my approach, but I think
you'll find lots of variability. Between cardiologists.
Typically what we do for my patients is they're
(08:14):
on high dose calcium channel blocker, high doses
of verapamil or diltiozum. I generally reduce
the dose of calcium blocker. Just prior to starting
the Mavicampton. So, you know, when we're in that
phase of getting approval, prior authorization,
arranging for shipping in those couple of weeks.
I may reduce the dose of counting blocker, see
(08:37):
how they tolerate it, and if they're fine on that
lower dose, go ahead and start the Mavic Hampton.
For patients on metoprolol, I generally leave
them at the dose. Sometimes I opt to reduce the
dose a bit. Then I wait for usually 12 weeks until
they reach a steady state. We've got the gradient
under control. The other things we look for, of
(08:58):
course, are the ejection fraction. The degree
of Tham, mitral regurgitation, diastolic function.
Make sure that things are all moving in the right
direction, and importantly, that the patient is
feeling better. And their symptoms are controlled.
At that point. We may need some adjustment in
blood pressure medication. We have seen patients.
(09:20):
As the LVOT obstruction is relieved that they
become hypertensive or more hypertensive. So we
may be doing some. Adjustment of their anti-hypertensive
therapy if they have hypertension. So we generally
try to do one thing at a time. And inevitably
they come to us and say, when can I get off of
my beta blocker and or calcium blocker, but more
(09:40):
often the beta blocker due to limiting side effects,
as you know. And so then we started slowly down
to high trait again, as long as the symptoms are
improved. The gradient is gone, they're at a steady
state, then we would slowly reduce the background
therapy. That's been our approach. How about you?
DR. AYERS (09:57):
Well, in full confession, given that
most of my learning about HCM came from you and
Dr. Day, I do something very similarly. You won't
be. You won't be surprised to hear.
DR. OWENS (10:06):
Excellent.
DR. AYERS (10:09):
I not a day goes by an HCM clinic when
I don't ask myself what would Anjali do. So just
so you know, again. So you mentioned following
the ejection fraction for these patients. One
of the things that's sort of cognitively difficult
for these patients is They'll feel so much better
with alleviation of gradient, but I'm sure you've
(10:31):
had a handful of patients that start to really
skirt into an ejection fraction of the high 40s,
low 50s. What are you doing for your patient who's
got an EF? We'll just make it right at 49. But
the gradients gone and they feel great. And how
are you having that conversation with the patient
about the meaning or... Absence of meaning about
(10:52):
systolic dysfunction in those instances.
DR. OWENS (10:55):
Great, wonderful question. So as you
know from the trial data, many patients with the
transient drop in ejection fraction to less than
50% on a CMI, many of them are asymptomatic. Just
as you said, it's picked up by that safety echo,
but they're feeling otherwise fine. Their gradient
is gone. So they do have a hard time wrapping
their head around the concept at times. Just as
(11:17):
they have. Difficulty wrapping their head around
the concept of down titration of dose at week
four. Or weak aid. When they're feeling very well
and the gradient is gone. So it's a similar conversation
that we have. And I think a lot of it is really
predicated on the original discussion that you
have with the patient. As you're signing them
(11:38):
up for the REMS protocol and to use Mavic Hampton.
And it's during that initial conversation. Where
we say this is a novel mechanism of action. Here's
how the drug works. And as a result of that, you
may reach a stage where you're... Hypo-contractile.
And we are going to temporarily stop. And then
(11:58):
restarted a lower dose should that occur. And
so I think. Setting expectations so that patients
are not disappointed and it doesn't seem like
it's coming out of the blue is important. And
so that's what I say, we've reached that point
where your ejection fraction's a little bit low,
it's not causing you heart failure, you're feeling
well otherwise, we are gonna temporarily hold.
(12:19):
And then restart after a follow-up echo shows.
Recovery of the ejection fraction to above 50.
Now we do have many patients. Who are living in
that kind of low to mid 50 range and they feel
very well. And we're not doing anything for them.
We're continuing their dose of Mavicamptan. But
if they drop transiently below, then we are temporarily
(12:40):
holding. As you know, this often happens in the
setting of paracysmal AFib. So we're very careful
to tell our patients when they're starting Mavicamptan,
we wanna know if you go into AFib. Don't sit at
home for weeks in the AFib and not let anybody
know. Call us and tell us. And will make moves
to get you back into sinus rhythm if the paroxysm
hasn't gone away on its own. And that puts them
(13:02):
at less risk, I think, to drop the EF in that
setting.
DR. AYERS (13:06):
And ballpark, how many patients have
you seen at this point as a percentile maybe who
have dropped their ejection fraction and required
either cessation of the drug entirely or a pause.
DR. OWENS (13:16):
Very few. So I've seen more in our
clinical trial population because we've been following
those patients for now four plus years. From the
Explorer cohort. And from the long-term extension
of the Valor trial. We've seen a couple of, you
know, a handful of patients from the clinical
trial setting. In our commercial population that
(13:38):
has been started on Mavic Hempstead since FDA
approval. It's been about two patients. And that's
out of... Close to 90 or 100. So it's below 5%,
probably around 2% if I had to guess. How about
you?
DR. AYERS (13:55):
We've got about 40 to 50 people on
drug right now at the ballpark and we had two
drops. One within the setting of a hospitalization
for heart failure. That was actually related to
the tricuspid valve going wonky, nothing to do
with the HCM. And the second one was, as you nailed,
patient who had some breakthrough of atrial fibrillation
(14:16):
and dropped the ejection fraction in that setting,
and is requiring some more aggressive care with
our electrophysiology team to try and manage that.
DR. OWENS (14:25):
Yeah, I think that's been pretty typical.
We of course always warn patients that a serious
intercurrent illness that's non-cardiac. May also
be a time where they may be particularly vulnerable.
And again, this is based off of what we've seen
in some of the clinical trial populations. So
we do warn the patients if you have a serious
infection, any other serious medical illness that
(14:47):
they should let us know so we can be vigilant
about potentially. Monitoring the EFR closely
or temporarily holding drug if we need to.
DR. AYERS (14:55):
Do you think there will be a role not
to get too far off the beaten path? For a reversal
agent at some point in patients as we get more
and more patients on drugs.
DR. OWENS (15:06):
Interesting concept. I think, you know,
at least in the preclinical studies that the effect
of the cardiac myosin inhibitors could be overcome
by inotropes for the most part. And so I think
if you really have someone who gets into trouble
and is clinically in shock, cardiogenic shock,
something like that, then you can probably use
inotropes to get over a lot of the effect. If
(15:29):
it's a case like a massive overdose of a CMI,
then the CMI is a massive overdose. Perhaps there
would be a role for a reversal agent. God forbid,
hopefully that doesn't happen, but it's always
a possibility. Um. So I'm not sure if we'll need
a reversal agent. What are your thoughts on that?
DR. AYERS (15:48):
There's some case reports coming out
of Boston, I believe, about a patient, Perry Transplant,
who had stopped meds pretty well before their
transplant and then had kind of an abrupt drop
in ejection fraction post-transplant that was
maybe related. Maybe not, we know how rocky it
can be coming out of transplant. I think they
did get a compassionate use in that instance,
(16:10):
I don't know all the details of the case. But
it certainly made me think as we get more and
more patients on drugs. What happens when they
come in with say a run-of-the-mill heart attack?
Are we going to need some way to reverse this
medication? And so I was selfishly using this
time to pick your brain about where the future
of that was.
DR. OWENS (16:29):
No, certainly transplant is a tough
one and I would. Wrongly suggest that anyone being
listed for transplant is taken off of a cardiac
myosin inhibitor. I think that those two do not
mix well. So certainly that would be the case.
You know, someone with a big acute myocardial
infarction, harder to know what we'll do in that
(16:50):
setting. I mean, certainly that will. Probably
occur with enough people on these drugs, then
we'll have to know if finotropes are. Temporary
MCS is enough. I think down the pike in preclinical
studies and certainly with next generation. CMIs
with a shorter half life like Afikampton that
could be a potential benefit for getting off of
(17:10):
the drug quickly if you need to that the half
life is a bit shorter. There may be other alternatives
that may come up. That would help with that issue.
DR. AYERS (17:20):
Similar to the drop an ejection fraction.
Another way that you can kind of fail to use that
word loosely a cardiac myosin inhibitor is to
have an ongoing gradient despite their How often
are you seeing that and are there any features
that in your mind predict that might happen? Maybe
it's elongation of the anterior leaflet, more
(17:41):
of a mid-cavatary gradient. Is there anything
you're seeing that's not really happening? Gives
you a clue. That this patient might not fly on
just cardiac myosin.
DR. OWENS (17:50):
Yeah, what I've seen so far is mainly
anatomy just as you alluded to. Very long abnormal
mitral valves where it's more than just hyperdynamic
LV function that's contributing to the LVOT obstruction.
And there's really a mechanical anatomic reason.
(18:10):
Those patients may not respond as well, at least
the few that we've seen. They are options, of
course, for surgery. And may opt to do so if they
don't feel better and their gradient is still
present. We have seen in a couple of those patients
that despite still having obstruction, in the
severe range by gradients that they feel better.
(18:32):
And their NT-proBMP has come down. And so in a
couple of those patients, they have opted to consider,
continue the CMI and not pursue surgery. But I
think patients should know that if their obstruction
is still present, still severe, and they still
have symptoms, that they really should be pivoted
over to surgery if their gradient isn't resolving.
(18:53):
The second group of patients, and again, it's
small, but a bit notable. Are our very large mess.
And I wonder if that may be due to dosing and
kind of upper limits of dosing. It's anecdotal
and it's a couple of patients, but they tend to
be large men. And so I wonder if there may be
(19:13):
an effect there. Hopefully we'll get more data
as the drug is expanded to more real world populations
where. BMI may be higher, comorbidities may exist
that may affect the efficacy of the drug.
DR. AYERS (19:27):
That's very interesting you say that.
We have one or two that still have significant
residual gradient. And I had unified them in my
head as mitral anomalies, as you had said, both
of them very long anterior leaflets, a little
bit of apical displacement. More than what you're
used to seeing. But now that you say that, they
both are. Higher BMI men, so it raises the question
(19:49):
do they need to be? A bigger dose. Very interesting.
DR. OWENS (19:52):
Yeah, and I think, you know, certainly
within the FDA requirements now this early after
approval. I am not suggesting in any way that
we go above the recommended dosing limits. But
as time goes on and we get more experience you
know perhaps there would be a role for doing off-label
treatment. But at this point I would say no. You
know stick with what the FDA has done. Approved
(20:13):
and for safety reasons to do that. There's also
the metabolizer status that may play a role. So,
you know, if you have a fast metabolizer who happens
to also have a BMI, like perhaps there's a small
segment of people that that's just not the right
dose for them. We're not checking PK values, as
you know, that's not mandated by the FDA. And
(20:34):
so. And some of those real world patients, we
just don't know what their drug concentration
is and what their drug exposure is.
DR. AYERS (20:43):
There have been some whispers that
I've heard about increased rates of atrial fibrillation
in this population after starting med. Do you
think there's any truth to that? Have you experienced
that? Do you think we just need more data at this
point? How are you viewing that situation?
DR. OWENS (21:00):
I think the jury's out. I'm not sure
what's going to happen with the AFib data and
the paroxysms of AFib in particular. I certainly
think we need more data with that regard, longer
term data and good reporting. Oftentimes patients
will have a paroxysm of AFib and not really mention
it, not really think it's that big a deal as long
(21:22):
as it resolves. But that is data that may be harder
to capture. Hopefully the Discover registry or
real world registries will be able to get some
of that information. We're of course instructing
our patients to let us know if they have more
AFib. But I'm not certain, you know, and then
when you look at the longer term data, for example,
(21:44):
the MRI and echo studies, We're. Certainly seeing
an improvement in left atrial volume index. One
would think that that would lead perhaps to decrease.
I think it's something to take note of and certainly
something to follow in the patients that have
it to see if a trigger or some other interaction
(22:07):
can be identified.
DR. AYERS (22:10):
All right. I have three crystal balls
questions to end here. We'll see how much you're
willing to bite off. Oh boy. My first question
is... Is this a disease modifying agent? Should
we as cardiologists be calling this a DMARD at
this point or not enough data?
DR. OWENS (22:28):
I think we need a bit more data. So
it's tantalizing to bite on that one. And say
it's disease modifying. But as you know, I trained
as a heart failure physician and so I really would
like to see some. Longer term. Outcomes data.
This is of course hard to get in an HCM population,
but I do think we need a bit more data before
(22:52):
we're willing to say this is a test. Modifying
drug. I think the Remodeling is notable. And it
certainly gives us. Pause to say that hopefully
this will be a disease modifying drug. But I don't
think I would say that just yet. The other thing
that's in my mind is I don't know whether or not
(23:15):
patients will need the same dose of CMI long term.
That they need up. Particularly in the obstructed
population. To get resolution of obstruction.
After that point, when patients are on four or
five years. I don't know if maybe perhaps we need
to reduce the dose to more of a maintenance dose.
(23:35):
We certainly need more data with regard to what
to do with these drugs longer term. We'll get
a lot of good data from the ongoing phase three
trials in non-obstructive HCM. That might inform
us more about what the long-term effects of the
drug are going to be in that population. So, I
would still stop short of calling them disease
modifying. I would say potentially disease modifying.
DR. AYERS (23:59):
Yeah, it's very exciting to think about
some of the new opportunities for our patients
that have been opened up. Say a patient with suboptimal
coronary anatomy for alcohol ablation. Getting
up. Pretty good response from CMI and maybe now
you think about two therapies at once, right,
rather than a this or that. A little bit above.
(24:21):
You see. A number of different scenarios where
you might have multiple therapies being utilized
for our patients.
DR. OWENS (24:28):
Most definitely. And I think another
population where, you know, dual SRT followed
by CMI might be beneficial are the patients who
have, you know, very severe symptomatic obstruction.
They undergo adequate. Septal myectomy. But then
end up with. Diastolic heart failure. And a very
(24:49):
stiff and thick ventricle that has normal systolic
function, but nonetheless their NT Pro is still
elevated, they still have severe symptoms. That's
another population that I think the CMIs may be
very useful. As you know, they affect all of the
myocardium. So, you know, not just the part that
was cut out by the surgeon, but the whole myocardium
is being affected by the drug. And I think those
(25:11):
patients may benefit. Significantly. We'll get
more data of course from audits and indications.
For that population.
DR. AYERS (25:18):
You read into my crystal ball before
I even got to the question and that is, what are
you looking for in the non-obstructive trial and
what do you think might happen? I know you're
partially handcuffed. Both as a PI and as a...
Heart failure physician who loves her data, but...
What do you think we're gonna see?
DR. OWENS (25:35):
Yeah, I think what we'll see is that.
Non-obstructive HCM is much more heterogeneous
than obstructive HCM. So I think that we need
better phenotyping. To allow for subgroups of
non-obstructive HCM that we understand more deeply
than we currently do. And there are some patients
(25:55):
with non-obstructive HCM who have accumulated
significant fibrosis, their ejection fraction
is already on the low end, they have more congestive
symptoms. And maybe even borderline cardiac output.
And as you know, with band of the right heart
cath, so I think we can get hemodynamic data to
help us. And those patients may benefit more from
(26:19):
SGLT2 inhibitor and more going towards the HFREF
route. Of medical therapy. Whereas other patients
with non-obstructive HCM still have quite a hyperdynamic
LVEF in the mid 70s. You know, big life left atria.
High filling pressures. And those patients I think
(26:40):
will benefit from the cardiac myosin inhibitors.
But I think it's a lot more difficult to pick
out. Who's going to benefit with non-obstructive
HCM. The other thing we have to consider in that
population is the high rate of comorbidities in
some of those patients. Including obesity and
other medical comorbidities that may affect their
(27:02):
response and the efficacy of CMIs. And we see
that a little bit in our obstructive population
in the real world now that we are treating patients
with higher BMIs or. Other medical issues that
may affect their exercise tolerance. And I think.
That will be amplified in the non-obstructive
population. So I think we have to be careful.
Particularly with enrolling for the clinical trials.
(27:24):
To see which populations may benefit.
DR. AYERS (27:29):
All right. Last question, I could do
this all day with you. I hope you know the clarity
of your explanation lives in my head, relatively
rent free all the time in clinic. But I will ask
just one more question of you and that is. Between
cardiac myosin inhibitors, afficamton, possibly
bringing more competition to the market, the non-obstructive
(27:49):
trial coming down the pipeline, more and more
patients feeling better, the genetic. Trials that
are rolling out. What are you most excited about?
In the HCM sphere right now.
DR. OWENS (28:02):
Well, that's a tough one. That is a
tough one. Um Well, you know, one thing you didn't
mention, there are some agents in preclinical
evaluations that will be hopefully coming to.
Phase one first in human. That actually have more
of a lucidropic. And less effect on systolic function.
(28:24):
And I'll leave that as a cliffhanger. But I'm
pretty excited about hearing more about those.
DR. AYERS (28:30):
Alright. Excellent answer. Thank you
for answering all my texts about patience when
I need it and thank you for all the training and
for your time I really love talking to you
DR. OWENS (28:39):
You're very welcome, Mike. You're too
sweet. Thanks again.
ANNOUNCER (28:47):
That was Dr. Michael Ayers and Dr.
Anjali Owens. For more information on HCMA, visit
4HCM.org. That's number 4HCM.org. This episode
was edited and produced by Ear Fluence. Thanks
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the Thick of It.
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