Circulation August 24, 2021 Issue

This week's episode features special Guest Host Victoria
Delgado, as she interviews author Qiang Zhang and Greg (who was
the editorialist and handling editor) as they discuss the article
"Towards Replacing Late Gadolinium Enhancement with Artificial
Intelligence Virtual Native Enhancement for Gadolinium-Free
Cardiovascular Magnetic Resonance Tissue Characterization in
Hypertrophic Cardiomyopathy."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the Journal and its editors. We're your
cohost. I'm Dr. Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, director of the Pauley Heart Center at
VCU Health in Richmond, Virginia. And Carolyn, this week's
feature actually is a magnetic resonance imaging paper, which you
know, of course, I'm very fond of. And these authors have come up
with a new methodology to get information equivalent to a late
gadolinium-enhanced exam without administering gadolinium. But
before we get to that feature discussion, how about we start in
with some of the other articles in this issue?


Dr. Carolyn Lam:


Yep.


Dr. Greg Hundley:


Well, how about if I go first? So Carolyn, the first paper I'm
going to discuss is from Dr. Paul Welsh from the University of
Glasgow, and it pertains to abdominal aortic aneurysms, which you
know can occur in patients who are ineligible for routine
ultrasound screening. A simple abdominal aortic aneurysm risk
score was derived and compared to current guidelines used for
ultrasound screening of abdominal aortic aneurysms.


Dr. Greg Hundley:


And so, this study comes to us from the UK Biobank, and they
examined participants without previous, and let's just abbreviate
this as AAA or AAA. So without previous AAA, we're split into a
derivation cohort of 401,820 individuals, and a validation cohort
of 83,000 individuals. An incident AAA was defined as a first
hospital, inpatient diagnosis of AAA, death from AAA, or a
AAA-related surgical procedure. And, of course, they used
multivariable Cox models to develop the derivation cohort, and
then apply that to the validation cohort.


Dr. Carolyn Lam:


Wow, Greg, that is a large number of people, the power of the UK
Biobank, huh? So, what did they find?


Dr. Greg Hundley:


Right. So, Carolyn, components of the AAA risk score were age,
stratified by smoking status, weight, stratified by smoking
status, any hypertensive and cholesterol-lowering medication use,
height, diastolic blood pressure, baseline cardiovascular
disease, and then diabetes.


Dr. Greg Hundley:


So, Carolyn, in the validation cohort, over 10 years of
follow-up, the C index, for the model for the USPSTF guidelines,
was 0.705, whereas, the C index of the risk score as a continuous
variable was 0.856. And in the validation cohort, the USPSTF
model yielded a sensitivity of 63%, and a specificity of 71%.


Dr. Carolyn Lam:


Okay, Greg, but what's a take-home message?


Dr. Greg Hundley:


Right, Carolyn. So the take-home message is that in an
asymptomatic general population, a risk score based on patient
age, height, weight, and a medical history may improve
identification of asymptomatic patients at risk for clinical
events from AAA. And also, these results highlight that further
development and validation of risk scores to detect asymptomatic
AAA are needed.


Dr. Carolyn Lam:


Wow, and that was a great summary with a lot more data in the
article, huh? Let's refer the readers to it. But for my paper, it
highlights the key role of histidine triad nucleotide-binding
protein 1, or HINT 1, in the pathogenesis of cardiac hypertrophy.


Dr. Greg Hundley:


Wow. Carolyn, so tell me a little bit more about HINT 1.


Dr. Carolyn Lam:


I thought you may ask. HINT 1 is a highly-conserved 14 kilodalton
protein that belongs to the histidine triad super family. It was
previously shown to play a role in diverse neuropsychiatric
diseases. Loss of HINT 1 increased susceptibility to
carcinogenesis in mice, suggesting, as well, a tumor suppressor
role. So recently, HINT 1 has emerged as a tumor suppressor with
multiple molecular mechanisms, involving regulation of apoptosis,
gene transcription, and cell cycle control.


Dr. Carolyn Lam:


Now, with that as a background, today's paper from
co-corresponding authors Drs. Ji, Xie and Han, from Nanjing
Medical University, used animal models and cell models of
hypertrophic growth, and found that HINT 1 deficiency aggravated
overload-induced cardiac hypertrophy and fibrosis and
deteriorated cardiac dysfunction in mice, whereas,
cardiac-specific HINT 1 over-expression attenuated cardiac
hypertrophy, and rescued cardiac dysfunction.


Dr. Carolyn Lam:


Furthermore, the more the authors uncovered Homeobox A5, or Hox
A5, as a HINT 1 target gene, which contributed to hypertrophy
through activating the TGF beta signal pathway. Combined, these
findings demonstrate HINT 1 may be a prognostic biomarker, and
this may establish a foundation for future investigation of its
potential as a therapeutic target for cardiac hypertrophy and
heart failure.


Greg Hundley:


Great, Carolyn. So, we get a hint for future cardiac hypertrophy.


Dr. Carolyn Lam:


Hahaha.


Dr. Greg Hundley:


Couldn't resist.


Dr. Carolyn Lam:


Bravo.


Dr. Greg Hundley:


Couldn't resist. So, Carolyn, my next paper comes to us from Dr.
Mark Gladwin from the University of Pittsburgh. And, as you know,
many patients with one of your faves, heart failure with
preserved ejection fraction have metabolic syndrome and develop
exercise-induced pulmonary hypertension. Now, increases in
pulmonary vascular resistance, in patients with HFpEF portend a
poor prognosis. This phenotype is referred to as combined pre-
and post-capillary pulmonary hypertension.


Dr. Greg Hundley:


And therapeutic trials of exercise-induced pulmonary
hypertension, and pre- and post-capillary pulmonary hypertension,
have been disappointing, suggesting the need for strategies that
target upstream mechanisms of the disease. And so, this work
reports novel rat exercise-induced pulmonary hypertension models
and mechanisms of pulmonary vascular dysfunction, centered around
the transcriptional repression of the soluble guanylate cyclase
enzyme in pulmonary artery smooth muscle cells.


Dr. Carolyn Lam:


Ooh, so much of this is of interest to me, from HFpEF to soluble
guanylate cyclase. Ah, all right, so what did they find, Greg?


Dr. Greg Hundley:


Right, Carolyn. So, in the HFpEF and in the pre- and
post-capillary pulmonary hypertension models, metabolic syndrome
contributed to pulmonary vascular dysfunction and
exercise-induced pulmonary hypertension through enhanced reactive
oxygen species and MIR193B expression, which downregulates
NFYA-dependent soluble guanylate cyclase beta-1 expression, and
adenovirus mediated NFYA over-expression and SGLT-2 inhibition
restored NFYA soluble guanylate cyclase beta-1 cyclic GMP
signaling, and ameliorated exercise-induced pulmonary
hypertension.


Dr. Greg Hundley:


So Carolyn, after all of that, these results uncover a molecular
explanation for the unsolved clinical associations linking
metabolic syndrome with exercise-induced pulmonary hypertension
in patients with pre- and post-capillary pulmonary hypertension,
as well as HFpEF.


Dr. Carolyn Lam:


Wow. That is super, Greg. Thanks. Now, other articles in today's
issue include a research letter by Dr. Schunkert on
identification of a functional PDE5A variant at the chromosome
4q27 coronary artery disease locus in an extended myocardial
infarction family.


Dr. Carolyn Lam:


There is a policy front paper by Dr. Lackey on applying decision
analysis to inform FDA's benefit risk assessment of ticagrelor
for primary prevention of myocardial infarction or stroke, based
on the THEMIS trial. There's an exchange of letters between Drs.
Olson and Reiffel regarding the article emulating randomized
controlled trials with non-randomized real-world evidence
studies, the first results of the RCT Duplicate Initiative.


Dr. Greg Hundley:


Great. Carolyn. Well, I've got two other papers. There's an ECG
challenge from Professor Macherey entitled, Wide QRS complex
bradycardia in a hemodynamically unstable young woman. And then,
finally, one of our nice perspective pieces from Dr. Armstrong
entitled, Extending the product label for ticagrelor: Looking
under the FDA hood. Well, Carolyn, now we're going to learn a
little bit more about that non-contrast method of MRI to get,
maybe, the equivalent to late gadolinium enhancement in patients
with hypertrophic cardiomyopathy.


Dr. Carolyn Lam:


And all by AI. Very, very cool. All right, let's go.


Dr. Victoria Delgado:


Hello, I'm Victoria Delgado, associate editor of Circulation, and
working at the University Medical Center, and I have the
privilege to welcome Dr. Zhang from the University of Oxford,
division of cardiovascular medicine, and first author of the
article published in Circulation, which presents a new technology
that has the potential to change our clinical practice, and how
do we assess myocardial tissue characteristics, particularly
fibrosis with cardiac magnetic resonance.


Dr. Victoria Delgado:


With us, we have also Dr. Greg Hundley from VCU Pauley Heart
Center, associate editor of Circulation, and host of Circulation
on the Run and editorialist of this article. And Greg has handled
this article in the review process and guided Dr. Zhang and
coworkers to finally get a very impactful, in my opinion, and
novel paper that has the potential to change clinical practice.
He will help us to put in perspective the main message of this
article. But first, Dr. Zhang, why don't you tell us briefly,
what is this new technology for myocardial tissue
characterization with cardiovascular magnetic resonance, and why
did you develop it?


Dr. Qiang Zhang:


Well, first, I want to say thank you very much for the
invitation. Well, as we know, CMR late-gadolinium enhancement, or
LGE, has been the imaging gold standard for micro tissue
catheterization. However, LGE requires the injection of a
contrast agent, which prolongs the scan, increase the cost, and
is cautioned in some patient groups. It is therefore desirable to
develop a contrast-free technique to replace LGE. A native or
pre-contrast CMR such as cine imaging, T1-mapping and the
T2-mapping are alternative means for myocardial tissue
characterization without the need for contrast.


Dr. Qiang Zhang:


And notably, T1-mapping can detect a wider range of pathology,
but its clinical application is hindered by confounding factors
and a lack of clear interpretation. So we thought that since MRI
is inherently multimodal and multiparametric, with different
modalities reflecting complimentary information about micro
tissue, therefore can we use the ones of an AI  method to
combine the enhanced pre-contrast and modalities to produce a
virtual LGE image without the need for contrast, and this leads
to our concept of CMR virtual native enhancement.


Dr. Victoria Delgado:


Excellent. And in which population did you evaluate this
technology? Why did you choose? So, can you tell us a little bit
the characteristics of the population where you choose to assess
the performance of this new technology?


Dr. Qiang Zhang:


Yes, so we validated this concept first on the hypertrophic
cardiomyopathy patients using the image data from HCMR study,
which is a larger multinational study. We trained the new network
models on about 2,700 images, and then we tested independently on
124 patient materials.


Dr. Victoria Delgado:


And what were the results? Can you summarize them for us to
understand what you found, how you evaluated the performance of
this new technology compared to classical late gadolinium
enhancement?


Dr. Qiang Zhang:


Yeah. So, we found that first, the VNE image had significantly
better image quality than the traditional LGE, and the secondly,
the VNE revealed characteristic HCM lesions in hypertrophic
segment and added the anterior and the inferior right ventricular
insertion point, and those VNE lesions were in high visual
spatial agreement with the lesions detected by LGE. And thirdly,
VNE correlated strongly with LGE in quantifying hyperintensity,
micro lesions, but also more subtle intermediate-intensity
lesions as often observed in the HCM patients.


Dr. Victoria Delgado:


Exciting. And now I would like to turn to Greg. You are a
renowned expert on CMR. What did this article attract you? What
were the main findings that you found interesting in this
article?


Dr. Greg Hundley:


Yes. Thank you so much, Victoria. And just first, before I get
started, I wanted to thank Zhang for sending us this work, and
his entire team really spanning several institutions around the
globe. Victoria, I want to thank you for leading this discussion.
And Victoria, we work as a team looking at imaging, and what's
very impressive is this caught multiple of us on the imaging
team, but also the editorial board. So want to thank you
Victoria. And then, finally, I want to thank Dr. Charlotte
Manisty and Jennifer Jordan who helped with the editorial.


Dr. Greg Hundley:


So, just to take a little bit of a step back in the year 2000,
Dr. Ray Kim, Dr. Bob Bono, Dr. Bob Judd at Northwestern
University, in Chicago, administered gadolinium contrast. It's an
extra cellular agent and they were examining myocardial
perfusion, and then they noticed if they took images 10 or so
minutes after that administration, they appreciated this late
enhancement of the myocardial tissue that was associated with two
things, one myocardial injury, and then, also, scar formation.


Dr. Greg Hundley:


And for the last 21 years, that technique has been very valuable
in assessing infarct size in those with ischemic cardiomyopathy,
and then also recognizing extracellular fibrosis or forms of
myocardial injury in a variety of non-ischemic cardiomyopathy
processes. And one of those is hypertrophic cardiomyopathy. And
so, Zhang and his group have been working on a technique that did
not utilize gadolinium anymore. And they based this on, really,
had two important features.


Dr. Greg Hundley:


One is, some examination of the T1 relaxation that's available
when you acquire magnetic resonance images, and then also
applying artificial intelligence to analysis of these images.
Those two factors allowed this investigative team to produce
images that are very similar to what we appreciate with
gadolinium enhancement in patients with hypertrophic
cardiomyopathy. And why is that significant? So administration of
gadolinium, we think about two things, again, that are an issue
with that.


Dr. Greg Hundley:


Well, one, we've got to give the contrast agent, and some
patients are not well-suited. If you have renal dysfunction, you
can develop nephrogenic systemic fibrosis, a scleroderma-like
syndrome when the gadolinium is not cleared, and it's stays in
your body a long time. The other thing we tend to worry about
much more recently was accumulation of gadolinium in the brain
stem. We don't know that that has an adverse effect, but we're
certainly aware of it.


Dr. Greg Hundley:


And finally, I guess there is a third point. There are a few
patients, one in 20 to 40,000 that have allergic reactions. So,
for all those patients that really can't get gadolinium, this is
another potential opportunity moving forward. The second point is
time. So during an MRI scan time, or process, we administer the
gadolinium. And remember what I said, we've got to wait about 10
minutes to then collect these images. Well, if you can have a
technique where you don't have to administer gadolinium, you get
the same administration and you don't have to wait that 10
minutes, we might be able to save a large amount of time. And you
say, well, 10 minutes, what does that mean?


Dr. Greg Hundley:


But if you're doing many patients during the day, that really
could equate to a big time-savings. So what attracted us to this
article? A technical innovation that perhaps may obviate the need
for the administration of gadolinium in many cases, and here in
these patients with hypertrophic cardiomyopathy, I think the
images were quite stunning in that they appreciated the extent of
the fibrosis and scar in patients with hypertrophic
cardiomyopathy to the same degree, and maybe even with higher
image quality than we had in the gadolinium-enhanced comparitors.


Dr. Victoria Delgado:


Yeah. I agree with all those comments, indeed. For these 20
years, there have been other developments, in terms of assessing
diffuse fibrosis with T1-mapping techniques after administration
of gadolinium, but also before administration of gadolinium. And
this technology Dr. Zhang and co-workers have shown actually
reduces the time of acquisition because you only need 15 minutes
to acquire the cine images and the T1 images. And the analysis is
not very long in terms of post-processing, because it's also very
short. As seen the paper was indicated.


Dr. Victoria Delgado:


And as you said, the administration of gadolinium enhancement is
not free of potential risks. And in these patients, for example,
we have hypertrophic cardiomyopathy that can undergo repetitive
evaluations during follow-up. The use of this imaging technique
can help to reduce the exposure to gadolinium enhancement.


Dr. Victoria Delgado:


Now, the question for you, Qiang, will be, what are the next
steps for you and your team to further develop this technique, to
further convince the community to implement this technique in
clinical practice, and that can have an impact in our management
of these patients with hypertrophic cardiomyopathy, or with other
patients on whom we also evaluate the presence of myocardial
fibrosis?


Dr. Qiang Zhang:


Thank you, Victoria. And thank you Greg, for the very insightful
comments. So we think that the immediate future work would be to
validate the VNE HCMR study clinical outcomes as a potential new
contrast-free biomarker for HCM patients. And in the meantime, we
are working on extending the method to other pathologies,
particularly myocardial infarction, for viability assessment.


Dr. Qiang Zhang:


And we also think that the concept of AI virtual contrast agent
maybe apply it to other post-contrast images, such as early
gadolinium enhancement and extracellular volume refraction
mapping, or even, maybe, first perfusion. And also in
collaboration with MR vendors, we plan to implement VNE as inline
sequence on the scanner to display lesions immediately after the
pre-contrast cine and the T1-mapping acquisitions.


Dr. Victoria Delgado:


Very interesting. And Greg, another group of patients, for
example, that I'm thinking of where this technology can be very
helpful, and you have expertise on this, are patients undergoing
treatment with chemotherapy, what we need to address, for
example, or to evaluate the presence of cardiac toxicity. Would
you see in this population the value of this technique, or how do
you see the future of these technique in clinical practice?


Dr. Greg Hundley:


Yeah. Great questions, Victoria. I think probably five things and
many of those Qiang has already just brought up. One, with the
current study, it's going to be great to follow these patients
over time and look at the outcomes. What did amount, presence,
location of the findings with this new technique, how did they
equate to outcomes in patients with hypertrophic cardiomyopathy?
So we're going to anxiously await that.


Dr. Greg Hundley:


I think once we move out of the current study, thinking about
other vendors, using this and acquiring images from General
Electric and Phillips, and multiple vendors around the world and
multiple field strengths, how do we going to understand the
findings there? I think another particular issue will be
different diseases as Qiang ha said, ischemic cardiomyopathy.
Well, what about amyloid? Victoria, you've mentioned using the
other possibility here is, can this technique help us produce
something similar to extracellular volume fraction measures? And
could that be used to identify interstitial disease processes?


Dr. Greg Hundley:


And, for example, as you mentioned, the fibrosis that's
associated with the administration of certain chemotherapeutic
agents or radiation therapy. I think another thing is, Qiang, can
we go back and use retrospectively-collected data? Can your
technique be modified so that many of the studies that have been
performed in the past, large population studies, like Mesa or a
Framingham or Jackson heart study, and could we use that to
develop forecasting and algorithms moving forward?


Dr. Greg Hundley:


And then, lastly, I think as you mentioned, the artificial
intelligence component of what you've described and how's that
can compare when Victoria and I look at the images, and could we
get into combining reads from one institution, reads from
another, reads from another, tracking outcomes? And so, when a
patient comes in and has a study performed, your artificial
intelligence, not only does it read that study and highlights the
increased signal in the myocardium, but then goes and looks at
outcomes across multiple sites, and what would that mean for a
given patient with a different condition? So, oh my goodness, the
horizon is just so expansive here. The future is very bright. And
just to congratulate you on, I really think this could be another
landmark technical innovation, so fantastic work.


Dr. Victoria Delgado:


Indeed. Thank you very much, Greg, for all these insightful
comments and these perspectives that we have in the future,
particularly with the use of this technique in retrospective
studies in large cities, that where we can develop these
algorithms. And I would like also to thank Qiang for submitting
your article to Circulation, for giving us the opportunity to
present this new technology and make this article, like the
landmark article, where there will be many other articles to
follow. We hope that you also choose us.


Dr. Victoria Delgado:


But with this, I would like to thank both of you, Greg and Qiang,
for the excellent discussion that we have had in this new
technology, based on artificial intelligence, that can identify
myocardial fibrosis without the use of gadolinium enhancement,
that maybe by now will be obsolete in the future, and that can
impact on how we do our clinical practice. Many thanks to all of
you and happy to discuss in the future other articles.


Dr. Greg Hundley:


Well, on behalf of Carolyn and myself, I want to thank our
speakers, and then also, wish everyone a great week. And we will
catch you next week On the Run. This program is copyright of the
American Heart Association, 2021. 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,
visit ahajournals.org.