Circulation December 20, 2022 Issue

This week, please join author Mads Liisberg and Guest
Host Mercedes Carnethon as they discuss the article "Clinical
Characteristics, Incidences, and Mortality Rates for Type A and B
Aortic Dissections: A Nationwide Danish Population-Based Cohort
Study from 1996 to 2016."


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
co-host. 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, Associate Editor, Director of the Poly
Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, today's feature paper is about aortic dissections and it's
the first nationwide population based study investigating the
clinical characteristic, incidents, and mortality based on
validated diagnosis of aortic dissection in a national patient
registry. You want to hear more? Well, you have to just keep
listening. Let's go on though first to discuss the other really
important papers in today's issue, shall we?


Dr. Greg Hundley:


Absolutely.


Dr. Carolyn Lam:


You know what, Greg? I'm going to start while you grab a coffee.
I want to talk about high sensitivity cardiac troponins and how
they have allowed the use of strategies in the emergency
department, for example, to rapidly rule out acute MI within one
to three hours and potentially facilitate early discharge of
low-risk patients. Now, the ability to rapidly rule out MI of
course depends on the turnaround time of these high sensitivity
cardiac troponin results from the central laboratory, which is
often delayed due to specimen transport and handling and all
these things.


So, point-of-care assays can reduce this turnaround time by even
40 minutes, and early studies have actually used frozen plasma
bio banks to assess these point-of-care assays... But no study
has evaluated these point-of-care assays with fresh whole blood
to safely rule out MI in the emergency department. That is until
today's paper. So in today's study led by corresponding other
Doctor Fred Apple from Hennepin Medical Center in Minneapolis,
Minnesota and his team, they aimed to derive and validate an
optimal high sensitivity cardiac troponin threshold concentration
using whole blood point-of-care troponin eye assay on a single
sample at presentation in the emergency department to identify
patients at low risk of index MI for potential early discharge.


Dr. Greg Hundley:


Fascinating study Carolyn. So point-of-care testing, high
sensitivity troponin from whole blood in the ED. So what did they
find?


Dr. Carolyn Lam:


Among consecutive emergency department patients from two
prospective observational studies with suspected acute coronary
syndrome, a point-of-care, whole blood, high sensitivity cardiac
troponin eye assay, the Atellica VTli provided a sensitivity of
98.9% and a negative predictive value of 99.5% for ruling out MI.
A single measurement using a cutoff of less than four nanograms
per liter for whole blood was successful in rapidly identifying
patients at low risk of MI cardiac and all cause death and
unplanned revascularization at 30 days.


Dr. Greg Hundley:


Very nice Carolyn, and could be quite practical. So Carolyn, my
next paper comes to us from the world of preclinical science and
it pertains to cardiac regeneration. So cardiac regeneration
after injury is limited by the low proliferative capacity of
adult mammalian cardiomyocytes. However, certain animals readily
regenerate lost myocardium via process involving
dedifferentiation, which unlocks their proliferative capacities.
So inspired by this concept, these investigators led by Professor
Patrick Hsieh from Academic Sinica, generated mice with inducible
cardiomyocyte specific expression of the Yamanaka factors
enabling adult cardiomyocyte reprogramming and dedifferentiation
in vivo.


Dr. Carolyn Lam:


Wow. So what did they find, Greg?


Dr. Greg Hundley:


Right, Carolyn. So two days following induction, adult
cardiomyocytes presented with a dedifferentiated phenotype, an
increase proliferation in vivo. Microarray analysis revealed that
the up-regulation of ketogenesis was central to this process. Now
adenovirus driven HMGCS2 over-expression induced ketogenesis in
adult cardiomyocytes and recapitulated cardiomyocyte
dedifferentiation and proliferation observed during partial
reprogramming. This same phenomenon was found to occur after
myocardial infarction, specifically in the border zone tissue.
And HMGCS2 knockout mice showed impaired cardiac function and
response to injury, and so in summary, Carolyn, these data
demonstrated the importance of HMGCS2 induced ketogenesis as a
means to regulate metabolic response to cardiomyocyte injury,
thus allowing cell dedifferentiation and proliferation as a
regenerative response.


Dr. Carolyn Lam:


Wow, that's so cool. From cell regeneration to autoimmunity in
this next paper. Now autoimmunity is increasingly recognized as a
key contributing factor in heart muscle diseases. However, the
functional features of cardiac autoimmunity in humans remain
undefined due to the challenge of studying immune responses in
situ. Now, these authors previously described a subset of c-Met
expressing memory T lymphocytes, which preferentially migrate to
cardiac tissue in mice and humans. In today's study, these
authors led by co-corresponding authors, Dr. Federica
Marielli-Berg and Saidi Mohidden from William Harvey Research
Institute, Barts and the London Faculty of Medicine and
Dentistry, and Queen Mary University of London, and their
colleagues performed in-depth phenotyping of peripheral blood T
cells in groups of patients with inflammatory and
non-inflammatory cardiomyopathies, patients with non-cardiac
autoimmunity and healthy controls... And they found that c-Met
positive T cells were selectively increased in the circulation
and in the myocardium of patients with inflammatory
cardiomyopathies.


The phenotype and function of c-Met positive T-cells were
distinct from c-Met negative T cells, including preferential
proliferation to cardiac myosin and co-production of multiple
cytokines. Further, circulating c-Met positive T cell
subpopulations in different heart muscle diseases identified
distinct and overlapping mechanisms of heart inflammation.
Furthermore, validation studies in experimental autoimmune
myocarditis showed that elevations of auto-antigens specific
c-Met positive T cells in peripheral blood, marked the loss of
immune tolerance to the heart. Importantly, disease development
could be halted by pharmacologic c-Met inhibition indicating a
positive role for these c-Met positive T cells.


Dr. Greg Hundley:


All right, Carolyn, as you always ask me. So what's the take home
message here?


Dr. Carolyn Lam:


This study demonstrates that the detection of circulating c-Met
positive T cells may have utility in the diagnosis and monitoring
of adaptive cardiac inflammation and additionally defined new
targets for therapeutic intervention when cardiac autoimmunity
causes or contributes to progressive cardiac injury... And this
is discussed in an editorial by doctors at Abplanalp, Merten, and
Dimmeler.


Dr. Greg Hundley:


Very nice, Carolyn. Wow. More fantastic preclinical science.
Well, in the mail of the bag today, there is a Research Letter by
Professor Burr entitled “Cannabis Inhalation Acutely Reduces
Muscle Sympathetic Nerve Activity in Humans.”


Dr. Carolyn Lam:


There's an ECG Challenge by Dr. Reddy entitled “Shortness of
Breath and Near Syncope During Exertion In a Child, When Patient
Worry Syndrome.” There's also a Perspective by Dr. Weitz on what
is the future of Factor 11 inhibitors.


Dr. Greg Hundley:


Well Carolyn, I'm looking forward to learning more about aortic
dissections and that large Danish population-based study. Wow.


Dr. Carolyn Lam:


That's great. Let's go Greg.


Dr. Mercedes Carnethon:


Well, welcome to this episode of Circulation on the Run. My name
is Mercedes Carnethon, an Associate Editor of Circulation, and
Professor and Vice Chair of Preventive Medicine at Northwestern
University. I'm really excited today to be here with the senior
author of a really exciting paper that we're featuring on
clinical characteristics, incidences and mortality rates for
aortic dissections type A and B, a nationwide Danish
population-based cohort study, and we have with us today Mads
Liisberg. So welcome today.


Dr. Mads Liisberg:


Thank you.


Dr. Mercedes Carnethon:


So thank you so much for joining us and really thank you for
sharing your important research with Circulation. This topic is
so critically important, particularly given the high mortality
rates associated with aortic dissections. Can you tell us a
little bit about the work that you and your co-authors did in
this important space?


Dr. Mads Liisberg:


Yes. Well actually the work originated when I started my PhD
thesis and we got a registry data dump from the Danish medical
registries and we found that almost none of our patients in the
registry were registered with a specific aortic dissection code.


So we did a validation study on the same time period from 1999 to
2006 where we went through all these medical records to ensure
that we had the right aortic dissection TC 10 codes on
population. Then we went a bit further and looked at the clinical
characteristics of this patient, 'cause that's one of the really
major things about Danish medical registries in our country, is
that we have access to not only every patient's specific in
hospital contacts, but also their medicine abuse, their drug use
based on a TC code. So we can go really deep into each and
everyone's drug history. When we did this study, we wanted to
find out if the incidence rates during this timeframe had
changed, which we find that it did, but also looking at mortality
rates because, as you said, it's really high risk disease to be
diagnosed with. So that's more the rationale for this study.


Dr. Mercedes Carnethon:


Thank you so much for sharing that. Certainly we know that the
mortality rates from this are very high. I note that you report
some changes over time between 1996 and 2016 in the incidents of
these types of aortic dissections. So what did you find about the
patterns of change in type A aortic dissections?


Dr. Mads Liisberg:


We found that it almost doubled from the beginning of our time
period to the last, and the question is why is this? 'Cause
that's one of the thing that the data doesn't reveal. We are only
able to see that the incidence actually rises, but is it because
that they are underdiagnosed in the beginning? Or is it because
that we are better diagnosing in the end of the study that really
are progressed?


Dr. Mercedes Carnethon:


That's a good question. I noted that when you studied the
correlates of aortic dissection, you identified a number of
characteristics and what stood out to me was the finding about
the strong association of hypertension. I'm less aware of
patterns of hypertension in the Danish population. Do you think
that the changes in the prevalence of hypertension in the
population contributed at all to these findings?


Dr. Mads Liisberg:


Well, most certainly, 'cause when you look at the prevalence of
hypertension throughout any person's lifespan, the older they get
the more likely they are to suffer from hypertension, and the
Danish population has aged quite a lot in recent years. So I
think that's one of the main reasons we find this, and also that
most of our arctic dissection patients are actually quite old,
which would correlate with hypertension as well.


Dr. Mercedes Carnethon:


One thing I really like, and you pointed this out, is really the
richness of the data that you have in your health system, and I
wonder, just going even a little deeper on the hypertension
question, given that it is the most common medical diagnosis
worldwide, were you able to study characteristics of hypertension
that would be more strongly associated with aortic dissection? So
for example, duration of hypertension, severity, prevalence of
hypertension control?


Dr. Mads Liisberg:


That's actually a funny question 'cause the last study of my
thesis, which hasn't been published yet or even submitted for
that fact, examines the correlation between use and the risk of
arctic dissection. On a very specific level, the way that
hypertension is treated mostly in Denmark is with your general
practitioner. So the way that we examine in studies like these,
is that we look at prescription drug use. So if we find that an
individual has a TC codes corresponding with anti-hypertensive
drugs, then we are able to code them as hypertensive patients.


Dr. Mercedes Carnethon:


Okay, thank you for that. I always... I'm an epidemiologist
myself, so I really love to see great population science studies
and this registry is large, you have long-term follow up and
you've got a great deal of data, but those people who feel as
though it's obviously not appropriate to make causal conclusions
around epidemiology and that perhaps epidemiologic findings
shouldn't be driving clinical decision-making. In response to
that, I think I would pose the question to you, which is how do
you see clinicians and providers using this information from your
observational study?


Dr. Mads Liisberg:


I think that's rather difficult. One of the findings that we
present is to pose it over mortality for type B dissections when
we exclude the 30-day mortality, but then we show that type A
dissections have almost a corresponding mortality rate compared
to a hypertensive cohort... And this finding is difficult to draw
any clinical conclusions from, but there's actually a Danish
randomized controlled trial just starting up in the next year. I
think it's called the Sunday trial, where they will include all
uncomplicated type B dissections and randomize them for treatment
or no treatment, and the issue here is that you'll probably be
over-treating some patients and under-treating others, but this
discussion with the uncomplicated type B dissection has been
ongoing for so many years. So it's difficult for me to just give
one golden answer.


Dr. Mercedes Carnethon:


Certainly, and I appreciate the caution as we certainly don't
want to overstep our findings. You did make a recommendation in
the conclusion that it might be beneficial to treat type B aortic
dissections more aggressively. Is this what you're alluding to,
based on the other study that you're referencing?


Dr. Mads Liisberg:


Yes, yes, definitely. We see some clinicians being more cautious
treating type B dissections with a TIVA or a surgery. So it's a
difficult thing when they're uncomplicated, why treat them? But
they can't be or become complicated quite easily and fast and
then it's a difficult thing, because should you have treated them
earlier? Or do you need to treat them now in their acute phase?
Or wait for a chronic phase? It's a really good question.


Dr. Mercedes Carnethon:


No, I appreciate that and what I really love are the types of
research studies that leave you with many more questions and next
steps, and so I would like to really sort of bring us to a close
with the big picture question, which is what do you see as the
next steps in this line of research, given really what we all
agree on is a very significant clinical problem.


Dr. Mads Liisberg:


We would really like to expand our database with even more
clinical data as of now and include any image diagnostics for our
cohort. So we're might be able to see any trends in our
modulation before the dissection occurs. If any of our patients
have any diagnostics done prior to being diagnosed.


Dr. Mercedes Carnethon:


I really want to thank you today for spending time talking with
us. I know that our readers rarely have an opportunity to hear
from everybody behind the scenes views on what the rationale was
for carrying out a paper and really how the authors themselves
hope that the paper will be used. So I really thank you for
sharing that with us today, Matts, on behalf of your co-authors,
this has been really a wonderful conversation, and thank you
again for sharing your research with the journal, Circulation.


Dr. Mads Liisberg:


Oh, thank you for having me in for accepting our paper.


Dr. Mercedes Carnethon:


So thank you so much to our listeners for listening to us on this
episode of Circulation on the Run. Please tune in next week as we
will have more exciting insights.


Dr. Greg Hundley:


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.