Circulation November 29, 2022 Issue

This week, please author Gemma Figtree and Associate
Editor Nicholas Mills as they discuss the Frontiers article
"Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease
Drug Development."


Dr. Greg Hundley:


Welcome listeners to this November 29th, 2022 issue of
Circulation On the Run. I am one of your hosts, Dr. Greg Hundley,
director of the Pauley Heart Center at VCU Health in Richmond,
Virginia.


Dr. Peder Myhre:


I am Dr. Peder Myhre from Akershus University Hospital and
University of Oslo in Norway.


Dr. Greg Hundley:


Well, Peder this week's feature discussion very interesting. It
is a state of the art review and it involves noninvasive plaque
imaging and really how we might assess plaques to evaluate
whether coronary artery disease is accelerating. Very important
information by a large group of clinician scientists that will
develop programs that, maybe, can be used in therapeutic drug
development.


Dr. Peder Myhre:


That's so interesting, Greg.


Dr. Greg Hundley:


Right. A great group of individuals all put together, but before
we get to that interesting feature discussion how about we grab a
cup of coffee and start with some of the other articles in the
issue? How about this week I go first?


Dr. Peder Myhre:


Go ahead Greg.


Dr. Greg Hundley:


Peder, these authors led by Marianna Fontana from University
College London Medical School sought to characterize changes in
the clinical phenotype of 1,967 patients with a diagnosis of
transthyretin cardiac amyloidosis over the last 20 years enrolled
and participating in the National Amyloidosis Center from 2002 to
2021.


Dr. Peder Myhre:


Oh yes, Greg, please. This cardiac amyloidosis we have to learn
more about it. Please, tell me what did they find.


Dr. Greg Hundley:


Right, Peder.


First, there's been a substantial increase in the number of
patients diagnosed with transthyretin amyloid in recent years.
This is associated with greater proportions of patients referred
following cardiovascular magnetic resonance imaging and bone
scintigraphy scans. Second, transthyretin amyloid patients are
often now being diagnosed much earlier in their disease process,
as evidenced by a shorter duration of symptoms prior to
diagnosis, milder stages of disease, and more favorable
structural and functional echocardiographic changes at the time
of diagnosis. Then, finally, mortality in these transthyretin
amyloids patients has improved substantially in recent times
aside from any potential benefits from disease modifying
treatment or participation in clinical trials.


Dr. Peder Myhre:


Wow. Greg, over the course of 20 years we have seen some
differences in the diagnosis or cardiac ATTR amyloidosis, so what
would you say are the take home messages from this paper, Greg?


Dr. Greg Hundley:


Right, Peder.


Transthyretin amyloid is now often diagnosed earlier in the
disease process with improved prognosis. I think, more data
needed to guide decisions on in whom and when to initiate
treatment and then which treatments should be used at each stage
of the disease. Peder, along with this article there's an
excellent editorial by Doctors Patel and Maurer entitled “The
Future for Patients with Transthyretin Cardiac Amyloid is, It's
Looking Brighter.”


Dr. Peder Myhre:


Okay. Greg, I'm going to continue in the field of clinical
research and this paper actually describes a new ablation
technique for ventricular tachycardia. Isn't that exciting?


Dr. Greg Hundley:


Absolutely.


Dr. Peder Myhre:


The paper comes to us from corresponding author Miguel
Valderrabano from Houston Methodist Hospital in Texas and is
entitled “Substrate Ablation by Multi-vein, Multi-balloon
Coronary Venous Ethanol for Refractory Ventricular Tachycardia
and Structural Heart Disease.” Ablation of ventricular
tachycardia, VT, in the setting of structural heart disease often
requires extensive substrate elimination, which is not always
achievable by endocardial radiofrequency ablation and epicardial
ablation is not always feasible. The left ventricle venous
circulation allows vascular access to reach intramural substrates
of VT in the context of myocardial infarction or non-ischemic
scar, where radiofrequency ablation has limited success. Greg, in
this study the authors enroll patients with ablation refractory
VT and used phonography and epicardial mapping to perform a
double balloon venous ethanol ablation. That is, by blocking flow
with one balloon and injecting ethnol via this second balloon.


Dr. Greg Hundley:


Peder, what a beautiful description and very interesting strategy
to address this situation.


What did they find?


Dr. Peder Myhre:


Greg, after the venous ethanol ablation vein maps and epicardial
maps showed elimination of abnormal electrograms of the VT
substrate an intracardiac echocardiography demonstrated increased
intramural echodensity at the target lesions of the 3D maps and
at one year of follow up VT recurrence occurred in seven
patients, which translates into a success rate of 84%. The
authors conclude that multi-balloon multi-vein intramural
ablation by venous ethanol ablation can provide effective
substrate ablation in patients with ablation refractory VT in the
setting of structural heart disease over a broad range of left
ventricular locations.


Dr. Greg Hundley:


Very nice, Peder. What a beautiful description. Excellent.


Well, this next paper Peder comes to us from the world of
preclinical science and these authors led by Professor Christine
Sideman from the Harvard Medical School evaluated alpha-kinase 3.
Now, alpha-kinase three is a muscle specific protein in which
loss of function variants cause cardiomyopathy with distinctive
clinical manifestations in both children and adults. At presence
the muscular functions of alpha-kinase 3 remain poorly
understood, so to address this dilemma these investigators
explored the punitive kinase activity of alpha-kinase 3 and the
consequences of damaging variants using isogenic human induced
pluripotent stem cell derived cardiomyocytes. Mice and human
patient tissues.


Dr. Peder Myhre:


Okay, Greg.


This sounds like impressive basic science work, so what did the
authors find.


Dr. Greg Hundley:


Right, Peder.


Damaging variance in alpha-kinase 3 encoding an abundant muscle
specific protein caused both neonatal and adult onset
cardiomyopathies and led to both ventricular dilation and
hypertrophy. Now, although alpha-kinase three contain an alpha
kinase domain the team showed that it lacks catalytic activity
and is really a pseudo kinase. Then finally, Peder, alpha-kinase
3 localizes to both the nuclear envelope of cardiomyocytes and
the M-band of the sarcomere where it regulates the expression and
localization of myomesins, myomesin 1 and myomesin 2, and
additional M-band proteins important for sarcomere protein
turnover.


Dr. Peder Myhre:


That is a beautiful summary, Greg. Since you did so well at
summarizing this difficult topic, I'm not going to ask you what a
clinical implications, but rather to take home messages here.


Dr. Greg Hundley:


Very nice. Glad you asked Peder.


First, alpha-kinase 3 cardiomyopathy may cause impaired
contractility and ventricular dilation due to miss localization
and dysregulation of myomesin proteins which are critical for
force buffering in cardiomyocytes. Next, alpha-kinase 3
cardiomyopathy may cause hypertrophy due to dysregulation of key
M-band proteins, which are important for sarcomere protein
turnover. Then finally, therapeutic strategies to restore
cardiomyocyte force buffering functions and sarcomere protein
turnover may ameliorate disease phenotypes in patients with
alpha-kinase three cardiomyopathy.


Dr. Peder Myhre:


Thank you Greg.


The next paper is also from the field of preclinical science and
it is about the Hippo-YAP signaling pathway which maintains sinal
atrial node homeostasis. It comes to us from the corresponding
author Jun Wang from the University of Texas Health Science
Center at Houston. Greg, this paper is not about hippos, but it
is about the Hippo signaling pathway, which is known to control
organ size and growth in animals and humans. These authors sought
to investigate this pathway in relation to the sinal atrial node,
i.e. The sinus node. As you know Greg, the sinal atrial node
functions as the pacemaker of the heart initiating rhythmic
heartbeats. Despite its importance the sinal atrial node is one
of the most poorly understood cardiac entities, because of its
small size and complex composition and function. To uncover the
function of Hippo signaling in sinal atrial node the authors use
knockout mice and a series of physiological and molecular
experiments including telemetry, electrocardiogram recording,
echochoreography, calcium imaging, immunostaining, ANA scope,
quantitative real time PCR, and western blotting.


Dr. Greg Hundley:


Wow, Peder, that sounds like quite an extensive series of
experiments. What did they find?


Dr. Peder Myhre:


Deletion of essential Hippo kinases caused increased fibroblast
proliferation and fibrosis in the sinal atrial node. They also
found evidence suggesting that Hippo signaling regulates calcium
hemostasis in pacemaker cells and that may be partially mediated
by the regulation of genes and coding key calcium handling
proteins such as RYR2. Finally, the demonstrated that deletion of
Hippo effectors in the sin atrial node can rescue the defect
previously described.


Greg, the take home messages is that Hippo signaling was found to
be an important regulator of the sinal atrial node homeostasis
and that this provide insights applicable to the treatment of
patients with sinus node dysfunction.


Dr. Greg Hundley:


Ah, beautifully done Peder. Beautifully done.


We've got some other articles in this issue. Let me tell you
about a Research Letter. It's from Professor Nazer entitled
“Targeted Screening for Transthyretin Amyloid Cardiomyopathy in
Patients with Atrial Fibrillation.” Then Tracy Hampton has a
whole series of cardiology news highlighting first that primary
cilia are critical for exercise induced muscle hypertrophy. This
is from the proceedings of the National Academy of Sciences.
Next, there's a discussion of whole body reperfusion techniques
to restore function in pig organs after death, that comes to us
from nature. Then lastly, there's a final article scientists
identify diverse pathogenic gene variants that lead to heart
failure from the journal science.


Dr. Peder Myhre:


Thank you, Greg.


Finally, there is one Perspective piece by Dr. Rajiv Agarwal from
Indiana University School of Medicine entitled
“Hydrochlorothiazide versus Chlorthalidone: What is the
difference?”


Now, let's move on to the feature discussion that I know you are
very excited about, Greg, to learn more about the non-invasive
plaque imaging in our frontiers of medicine.


 


Dr. Greg Hundley:


You bet.


Well listeners, welcome to this feature discussion today on
November 29th and we have with us Dr. Gemma Figtree from Sydney,
Australia and our own associate editor, Dr. Nick Mills from
Edinburgh, Scotland. Welcome to you both. Listeners, this is a
really interesting feature discussion. It's one of our Frontiers
articles that combines where we are in the past, but also where
we want to move in the future and a very nice comprehensive
review with many articles.


Gemma, can you describe for us the genesis really of this article
and what you've been working on?


Dr. Gemma Figtree:


Thanks so much, Greg. Look, I think it's very exciting times at
the moment and it's a really important time for all of our
community to actually get together in this space. We are driven
by trying to make a more efficient process for drug discovery and
translation to occur and to basically move into humans in the
space of coronary artery disease. We've actually known,
obviously, for a long time that the underlying process driving
heart attack, but we've not been able to image and treat the
actual underlying disease. What this article focuses on is how we
actually merge top current technology with policy and approval of
drugs. We are very excited about the team of over 20 different
institutes around the world trying to work on the best measures
of corona artery disease as the disease itself.


Dr. Greg Hundley:


Very nice. Now, help us understand different techniques and why
is this a frontier?


Dr. Gemma Figtree:


Look, I think it's a mixture of the fact that, obviously, we're
getting great advances in noninvasive imaging techniques that
allow us to actually measure plaque burden, but also plaque
characteristics. In the case of drug translation this is an
absolutely fundamental piece. You can transform a clinical trial
where you can look at the underlying pathology and be able to
enrich trials or be able to look at the effect of trials of a new
drug in humans.


It's really important to acknowledge the fact that humans are
really the only animal on the planet that get corona artery
disease itself. To be able to translate some of the exciting new
drugs that target the plaque itself and work synergistically with
some of our agents on cholesterol, and blood pressure, et cetera,
we really need to have these measures of coronary artery disease
itself. It's a combination of the technology, but also how we
apply it to a clinical trial and then how do we work with our
regulatory authorities and policy advisors around getting this
into humans. We really aiming to try to accelerate the
development of drugs that can try to tackle our greatest burden
of cardiovascular disease around the world.


Dr. Greg Hundley:


I'm hearing cardiovascular disease, I also heard in their imaging
and lots of different modalities, and then I heard regulatory
bodies. Are you thinking maybe we need standards?


Dr. Gemma Figtree:


That's exactly right. I think, importantly, whilst there's a lot
of exciting technology and a lot of us are pursuing potentially
different avenues of this we also need to be able to coordinate
and develop a simple and harmonized approach that's able to be
applied across the world in an equitable fashion. Whilst we,
obviously, have developing exciting new toys we have to make sure
that a measure that we want to work with regulatory authorities
is able to be applied in all of our countries around the world to
make sure that the drug development is applied in an equitable
fashion.


Dr. Greg Hundley:


Very nice. Well listeners, next we're going to turn to our
associate editor, Dr. Nick Mills. Nick, you evaluate many
manuscripts. What attracted you to this particular paper? Also,
help us put it in the context of why you think it's a new
frontier that is emerging or needs to emerge in cardiovascular
disease.


Dr. Nick Mills:


Yeah, thanks Greg.


Three things, the expertise of this group, the focus and novelty
of the topic, and the fact that it's a really timely issue Gemma
just outlined. Gemma a phenomenal job bringing together people
from all over the world to tackle this area that includes imaging
expertise, drug development expertise, industry that gives it a
very balanced and diverse range of views and marks it out from
other reviews that focus on particular imaging modality.
Novelty's really important, but timeliness as well. We've seen in
the last five years major breakthroughs in the treatment of
diabetes and heart failure. But, drug development of coronary
heart disease is stalling. I cannot remember the last time I went
to a really exciting late breaking trial on a new development for
coronary heart disease that has changed the outcomes for
patients. We do need to rethink.


Gemma's absolutely right, that requires us to work with
regulators to stimulate industry involvement in drug discovery,
and delivery, and testing. This is occurring at a time where
we've got more fabulous imaging modalities then we've ever had
before. Critically, they're noninvasive. They're easy for
patients, they're easy for serial testing, and that really opens
up many opportunities. It's the fact that it's timely, novel,
great expertise, and also really exciting area for cardio of
medicine.


Dr. Greg Hundley:


Very nice. Well listeners, we're going to go back to Gemma.
Gemma, what do you think are some of the next research studies
that we need to perform to support what we're trying to indicate
today in this Frontiers article?


Dr. Gemma Figtree:


Yeah. Thanks very much, Greg.


I think, ultimately, the features that need to be taken into
consideration for a surrogate endpoint to be approved by our
regulatory authorities need to be considered. There are many drug
companies, but also individual investigators with ideas of drugs
to take forward. What we need to do is make sure for all those
studies that we're actually working together and ideally having a
harmonized endpoint for use there. I think, working early with
regulatory authorities is going to be key.


I think, if you actually, within the tables that are presented in
the paper we demonstrate very clearly that these measures of
plaque, particularly, the CT coronary angiography measures of low
attenuation plaque are pretty ready for consideration by
regulatory authorities. I think, agents that we already know work
to reduce mortality, such as statins, we know that they actually
have direct effects on plaque both from a pathophysiological
perspective, but also from these imaging studies. We know that
that change in the plaque characteristics and volume predict the
outcomes.


In a sense, we've got a fabulous array of data already. In fact,
new agents that have come through have also demonstrated effects
on these measures. I think, by bringing all of this together in
this article we're already in a position to work with regulatory
authorities to see what is needed next. I think, listening to
that's going to be very important. I do think that the next steps
are really going to be working with effectively, I guess, our
colleagues to make sure that we don't continue to rapidly advance
the measures whilst losing the opportunity to work with
regulatory authorities.


In answer your question about the research side of things, I
think, as we gather more and more information about this we have
to make sure that phase two studies are then linked and we can
retrospectively see how they predict the outcomes in phase three
studies, but I firmly believe that we're in a position that over
the next couple of years we should be able to do harmonized
approaches at phase two studies and then as a whole community be
able to look at how that predicts outcome and work with our
regulatory authorities to get more confidence in these endpoints
as key. This is all driven by my clinical observations and
interest in people who look up and say, "Why me" when they're
having a heart attack? In our community where we're getting very
good primary prevention we see up to 25% of our heart attack
patients having plaque events and catastrophic heart attacks
without those traditional risk factors that would've worn them.


Part of this is also opening up avenues for driving new
diagnostic tools that can pick up the disease itself. Picking
up... Treating coronary disease as the disease and using that for
diagnostic and therapeutic purposes, I think, is a great
opportunity to tackle this great burden that we're currently not
winning with.


Dr. Greg Hundley:


With the group that you had assembled were there any primary
suggestions on how to unite some of these efforts on a global
scale? I really liked, very early in our conversation today, you
mentioned that and I wondered what this collective you assembled
may have suggested.


Dr. Gemma Figtree:


Yeah. Look, I think at the moment it is a collection of experts.
I haven't quite figured out the name for such a thing, but we are
also working with some of the leading organizations now to try to
also make sure we get their auspicing of the concepts and how to
best do that. I think, by not coming out of one particular
organization and evolving from the members itself, and in
particular, having industry and regulatory authorities involve
and drug discovery experts right from the beginning has been
fantastic. Also, making sure that we have that pragmatic approach
and that consideration of equitable access. Particularly, making
sure that any phase two trial can be done or enrichment for phase
three trial can be applied right around the globe and make sure
we get diversity of patients enrolled in these studies.


Dr. Greg Hundley:


Very nice. Coming back to you, Nick, any additional thoughts to
build on Gemma's comments here?


Dr. Nick Mills:


Well, to say as someone who's worked in the field of cardiac
biomarkers for many years and felt that we could tackle this with
the regulators and drug delivery, but I've seen inflammatory
biomarkers, lipoproteins come and go without changing. I think,
it's just a really exciting opportunity that we now have the
ability to phenotype an image, coronary artery disease
noninvasively, but a highly specific surrogate endpoint that
we've never had before. It's why I'm starting to do research into
DT.


Dr. Greg Hundley:


Very nice. Well listeners, we want to thank Dr. Gemma Figtree
from Sydney, Australia and our own associate editor, Dr. Nick
Mills for bringing us this really provocative Frontiers article
highlighting a new strategy. Bringing together regulators,
leading researchers, and industry to advance new methodologies
and trying to tackle globally how we might address
atherosclerosis.


Well, on behalf of Peder, Carolyn, and myself we want to wish you
a great week and we will catch you next week on The Run.


This program is copyright of the American Heart Association 2022.
The opinions expressed by speakers in this podcast are their own
and not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.