Circulation December 1, 2020 Issue

This week's episode features author Torbjørn Omland and Senior
Guest Editor Vera Bittner as they discuss the artile "Growth
Differentiation Factor-15 Provides Prognostic Information
Superior to Established Cardiovascular and Inflammatory
Biomarkers in Unselected Patients Hospitalized with COVID-19."


TRANSCRIPT BELOW:


Dr. Carolyn Lam:


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


Dr. Greg Hundley:


I'm Dr. Greg Hundley, Director of the Pauley Heart Center at VCU
Health in Richmond, Virginia. Well, Carolyn our feature this week
gets into inflammatory biomarkers in patients that have been
hospitalized with COVID-19, but before we get to that, how about
we grab a cup of coffee and work through some of the papers in
the issue. Would you like to go first?


Dr. Carolyn Lam:


Absolutely. With both the coffee and the papers. So great, for
this first paper, have you thought about concentric versus
eccentric cardiac hypertrophy? We traditionally associate them
with pressure versus volume overload respectively in
cardiovascular disease, both though conferring an increased risk
of heart failure. These contrasting forms of hypertrophy are
characterized by asymmetric growth of the cardiac myocytes in
mainly width or length respectively. However, the molecular
mechanisms determining myocyte preferential growth in width
versus length remain poorly understood.


Dr. Carolyn Lam:


That is until today's paper, and it is from Dr. Kapiloff from
Stanford University, and Dr. Rosenfeld from UCSD, School of
Medicine and their colleagues, and what they did was used primary
adult rat ventricular myocytes, as well as Adeno associated virus
mediated gene delivery in mice, to define a regulatory pathway
controlling pathological myocyte hypertrophy, and they found that
asymmetric cardiac myocyte hypertrophy is modulated by serum
response factor phosphorylation, constituting an epigenomic
switch balancing the growth in width versus length of adult
ventricular myocytes In vitro, and In vivo.


Dr. Carolyn Lam:


Serum response factor phosphorylation was bi-directionally
regulated at signalosomes organized by the scaffold protein
muscle, A kinase anchoring protein beta. This newly identified
molecular switch controlled a transcriptional program responsible
for modulating changes in cardiomyocyte morphology that occurs
secondary to pathological stressors.


Dr. Greg Hundley:


Very nice, Carolyn. So switches controlling this transcriptional
program. Tell us a little bit, and bring us back to the clinical
relevance of this and starting with that concentric versus
eccentric hypertrophy?


Dr. Carolyn Lam:


I thought you may ask. The identification of a molecular
mechanism regulating that asymmetric cardiomyocyte growth, really
provides a new target for the inhibition of pathological cardiac
hypertrophy. Studies in mice using these Adeno associated virus
based gene therapies to modulate that signalosome, really
provided proof of concept for translational potential in the
treatment of pathological cardiac remodeling and prevention of
heart failure.


Dr. Greg Hundley:


Oh, wow. Very nice, Carolyn. Well, my first paper comes to us
from Professor Dirk Westermann from Hamburg, and focuses on
cardiogenic shock patients, and veno-arterial ECMO, the results
from the international multicenter cohort study. So Carolyn this
study evaluated data from 686 consecutive patients with
cardiogenic shock treated with VA ECMO with or without left
ventricular unloading using an Impella, and they conducted this
at 16 tertiary care centers across four countries. They examined
the association between left ventricular unloading and 30 day
mortality.


Dr. Carolyn Lam:


Huh, so what did they find?


Dr. Greg Hundley:


Okay. Carolyn. Well, left ventricular unloading was used in 337
of the 686 patients enrolled, and after propensity matching 255
patients with left ventricular unloading were compared with the
255 patients without left ventricular unloading. In the match
cohort, left ventricular unloading was associated with lower 30
day mortality without differences in the various subgroups.
However, complications occurred more frequently in patients with
left ventricular unloading, like severe bleeding, which happened
in 38.4% versus only 17.9% in those without unloading. There was
also access-related ischemia and renal replacement therapy.


Dr. Greg Hundley:


So Carolyn, the take-home message from this International
multi-center cohort study, is that left ventricular unloading is
associated with lower mortality, and cardiogenic shock patients
treated with VA ECMO, despite higher complication rates. In the
absence of randomized trial data these findings support the use
of left ventricular unloading and cardiogenic shock patients
treated with VA ECMO, and call for further validation, ideally in
a randomized controlled trial.


Dr. Carolyn Lam:


Very nice. Well for my next paper, Greg, it's all about desmin.
Now we know that mutations in the human desmin gene caused
myopathies and cardiomyopathies. Well, today's authors, Dr.
Hermann and Schroeder from University Hospital Erlangen in
Germany and Dr. Lilienbaum from University of Paris and France
and their colleagues, report an adolescent patient who underwent
cardiac transplantation, due to restrictive cardiomyopathy caused
by a heterozygous R406W desmin mutation. Sections of the
explanted heart were analyzed with antibodies specific to
406W-desmin, and to intercalated disc proteins. Effects of this
mutation on the molecular properties of desmin were then
addressed by cell transfection and In vitro assembly experiments.
They further generated these desmin mutation knock-in mice
haboring the orthologous form of the human, R406W-desmin.


Dr. Greg Hundley:


So Carolyn, what did they find?


Dr. Carolyn Lam:


Well, they demonstrated a novel pathomechanism in which
cardiotoxic R406W-desmin, could adapt dual functional status with
the abilities to integrate into the indogenous intermediate
filament network, and to cause formation a protein aggregates.
This R406W-desmin modified the extra sarcomeric cytoskeleton,
such that desmin filaments were not anchored to desmosomes
anymore. Thereby destroying the structural, and functional
integrity of intercalated discs.


Dr. Greg Hundley:


What are the clinical implications?


Dr. Carolyn Lam:


Well, since these cardiotoxic desmin mutations could affect the
integrity of intercalated discs, thereby inducing conduction
defects and malignant arrhythmias, they suggest early
implantation of pacemaker, or cardioverter defibrillator devices,
may be considered to prevent certain cardiac death in patients
with these mutations. Furthermore, state-of-the-art basic
molecular risk stratification of desmin mutations may encompass a
multidisciplinary experimental approach as exemplified by the
approach taken here, which comprises assessment of the tissue
pathology in conjunction with genome analysis and desmin assembly
studies as well as patient mimicking cell and animal models for
the In vivo validation of these mutations.


Dr. Greg Hundley:


Well, fantastic, Carolyn. Well, my next paper comes to us from
Dr. Ravi Shah from the Massachusetts General Hospital. This study
evaluated 2,330 white and black young adults, average age of 32
years, in the Coronary Artery Risk Development in Young Adults,
or the cardiac study, to identify metabolite profiles associated
with an adverse cardiovascular disease phenom that included,
myocardial structure and function, fitness, vascular
calcification, and then also mechanisms, and other cardiovascular
outcomes that would occur over the next two decades. Statistical
learning methods, including elastic nets and principal component
analysis, and Cox regression generated parsimonious metabolite
based risk scores, validated in over 1800 individuals in the
Framingham Heart Study.


Dr. Carolyn Lam:


Wow. What did they show, Greg? Wow, that's a lot of work.


Dr. Greg Hundley:


Yeah. So Carolyn, the authors found two multiparametric
metabolite-based scores linked independently to vascular, and
myocardial health. With metabolites included in each score
specifying microbial metabolism, hepatic steatosis, oxidative
stress, nitric oxide modulation, and finally collagen metabolism.
Over nearly 25 year median follow-up, and cardia, this metabolite
based vascular score, and the myocardial score, and the third and
fourth decade of life were associated with clinical
cardiovascular disease. Importantly, the authors replicated these
findings in 1,898 individuals in the Framingham Heart Study
followed over two decades, such that young adults with poor
metabolite based health scores had higher hazard ratios of future
cardiovascular disease related events.


Dr. Carolyn Lam:


Oh wow. Greg, what an elegant study with both development and
validation cohort evaluating the metabolome.


Dr. Greg Hundley:


Yes. Carolyn. So metabolic signatures of myocardial, and vascular
health in young adulthood specify known novel pathways of
metabolic dysfunction, relevant to cardiovascular disease
associated with outcomes in two independent cohorts. So these
data suggests that efforts to include precision measures of
metabolic health in risk stratification to interrupt
cardiovascular disease at an early at stage, are warranted.


Dr. Carolyn Lam:


Wow. So interesting. Other very interesting articles in today's
issue, there's an In Depth article by Dr. Angiolillo entitled,
“The Antithrombotic Therapy for Atherosclerotic Cardiovascular
Disease Risk Mitigation in Patients with Coronary Artery Disease
and Diabetes.” There's also Research Letters, one by Dr. Sultan
on, “The Longterm Outcomes of Primary Cardiac Lymphoma” and one
by Dr. Wang on, “Loss of Phosphatase and Tensin Homolog Promotes
Cardiomyocyte Proliferation and Cardiac Repair Following
Myocardial Infarction.”


Dr. Greg Hundley:


Great, Carolyn. Well, I've got a couple other articles in this
issue as well. One is by Professor Ganesan Karthikeyan who has an
On My Mind piece entitled an “Alternative Hypothesis to explain
Disease Progression in Rheumatic Heart Disease.” Dr. Stuart Chen
has an ECG challenge entitled, “Alternating QRS Duration and a
Normal T-waves. What is the mechanism?” Then finally, Carolyn, a
series of Letters to the Editor, one by Dr. Peterzan and the
other by Dr. Mehmood regarding the prior published article,
entitled “Cardiac Energetics in Patients with Aortic Stenosis and
Preserved Ejection Fraction.” Well, Carolyn, how about we get
onto that feature article and learn more about inflammatory
biomarkers in hospitalized patients with COVID-19?


Dr. Carolyn Lam:


Yes. Let's go. Greg.


Biomarkers are really playing an increasingly important role in
cardiovascular disease, and even in the current COVID 19
pandemic, there's been a lot of news about how biomarkers such as
traponin may be prognostic, and in fact, we're all wondering
about maybe even newer biomarkers. In fact, today's feature
discussion does bring to light one of the newest, and in fact,
this is the first publication on the role of Growth
Differentiation Factor 15 or GDF-15 in COVID-19. We're so pleased
to be discussing this with the corresponding author, Dr. Torbjørn
Omland from University of Oslo, in Norway, as well as our senior
guest editor, Dr. Vera Bittner from University of Alabama at
Birmingham. So welcome both. Tobjorn, could you tell us a little
bit about GDF-15 and what made you look at it, and what did you
find?


Dr. Torbjørn Omland:


Yeah, so GDF-15, that's a very interesting biomarker. It's
considered a biomarker of biological aging cellular stress, and
perhaps also the inflammation, and tests being studied within the
cardiovascular field for some years now, and it has been shown to
be a strong prognostic indicator across the cardiovascular
spectrum, actually. So it is a new biomarker in one sense, but
there are some data already in the cardiovascular field.


Dr. Carolyn Lam:


Not in COVID. So this is the first study to really look at its
prognostic value in COVID 19. So congratulations Torbjorn, and if
I may also to the first author, Dr. Peter Meer, a good friend as
well, but please, could you tell us about your study and what you
found?


Dr. Torbjørn Omland:


Yes. So when the COVID pandemic hit Norway in the spring, we
thought that we should plan a prospective biomarker study. So we
had to really fast track approval by the IRB and so forth, and
we're able to actually cover most of the patients that were
hospitalized in our hospital, Akershus University hospital, which
is right outside of Oslo, and it's a pretty large hospital by
Norwegian standards. It covers about 11% of the Norwegian
population.


Dr. Torbjørn Omland:


So in that period, when we were including, we had 136 patients
hospitalized with confirmed COVID 19, and we have biobank bank
samples from 123 of these, and then there have been reports from
retrospective studies, first from China, that seemed to suggest
that markers like cardiac troponin, Anti-Troponin T, and Ferritin
were associated with outcome, but those studies were prone to
selection bias in that the measurements were performed in the
most sick patients. So in this study we included all patients and
then we thought we should examine a broad panel of biomarkers,
and that included Interleukin 6, CRP, Procalcitonin, Ferritin,
and the D-dimer Cardiac troponin, and N-terminal pro B, and
GDF-15.


Dr. Carolyn Lam:


Wow. Thank you, Torbjorn. Even before you carry on with the
results, can I just say having visited your hospital in pre-COVID
days, I can only imagine what a work of love this was to do it
prospectively. Any particular experiences to talk about, to get a
fast-track even in the midst of to perform a well done
prospective study, that must have taken a lot.


Dr. Torbjørn Omland:


Yes. But it's also interesting in that the whole sort of ablation
on Norway was very much into this from the highest political
level. Also, the decision that the older research on COVID should
be prepared to retire, then the IRB had an eight hour and
deadline for them to approve or not approve the study. So that's
went surprisingly smoothly, I must say.


Dr. Carolyn Lam:


Wow, that's great. So what did you find?


Dr. Torbjørn Omland:


Yeah, so we found that among these biomarkers, several seem to
predict outcome, and the primary end point of this study was to
combined end-point of the hospitalization in the ICU, or death.
We found that also markers like cardio traponin, BNP, ferritin,
and the D-dimer and so forth, in univariable analysis, were very
associated with outcome, but when we perform a more
comprehensive, mostly variable modeling, then the prognostic
value of some of these markers disappeared. In contrast, for
GDF-15, it seemed to perform very strongly, both on the baseline
sample, and interestingly also it increased in those reaching the
primary end-point during the hospitalization. So it provided a
very strong and independent information also when we adjusted for
clinical risk scores, like the NEWS score. So that was a very
pleasant surprise to see that there was one marker that's
actually performed so well. The other marker that's also
performed well was Ferritin.


Dr. Carolyn Lam:


Very interesting, and so the new score being the National Early
Warning Score. Thank you. Verra, I really love to bring in your
thoughts. I mean, could you take us behind the scenes with the
editors? What did you think when you saw this paper?


Dr. Vera Bittner:


As you know, I mean, a lot of journals have been inundated by
COVID papers, and so this one stuck out to us, because it's the
first time that we had seen that anybody linked GDF-15 to a COVID
population, even though it has been out in the literature for
ACS, and in my prognostication, and in a healthy populations, and
in chronic coronary disease populations, heart failure, and so
on. So this is the first time that we've seen it applied there.


Dr. Vera Bittner:


Then I would echo some of the things that Torbjorn said, that we
were also impressed, that it was prospective, because when you
look at some of the other biomarker studies, what was prognostic
in one with then not shake out the other one, because either
different variables were included in the models, because the
population's differed. So to have something that was
representative of the population that was actually admitted to
this, Norwegian Academic Hospital, stood out to us. So we're
excited to get this paper basically for circulation, and hope
that it also will be impetus for future research.


Dr. Carolyn Lam:


Thank you so much for sharing that end for helping us publish
such a beautiful paper. Did you have some questions for two of
your own?


Dr. Vera Bittner:


Yeah. So what stuck out to me is that you had this a whole crew
of biomarkers, and then when you looked ultimately at the final
model, there were two that were standing out, that was ferritin,
and it was the GDF-15, and then when I looked at your graph, it
looks like not only did these biomarkers measure different
contrasts, but their time-course also seemed to be different, and
so I was just wondering whether you had thought about, maybe
using these to joint the model outcome, and whether we might even
be able to get more information that way.


Dr. Torbjørn Omland:


I think that's an excellent suggestion, and as you correctly
pointed out, they do have different sort of profiles and ferritin
being an acute phase reactant, having various sort of dramatic
early rise whereas we see that GDF-15 increased progressively
during the course of hospitalization in the most severe patients.
I think when combining them, is actually a great IMT that we
should look further into.


Dr. Carolyn Lam:


Very nice. Torbjorn, if I could, I've got a couple of questions
too. So 123 patients, 35 of whom had the primary outcome, right?
So that may be sort of seen as, is this too small? and they're
all hospitalized patients. So could I ask, what do you predict
maybe seen in a larger population or outside of Norway or in a
non-hospitalized population?


Dr. Torbjørn Omland:


So as you say, we were early with this report, but since it was
submitted, there has been a couple of smaller studies that seemed
to confirm our results. So that is reassuring, but of course we
would like to have studied this in logical patients. We are in
touch with the other biobank samples that could possibly confirm
the data. So that's one obvious step. Then it's very interesting,
as you say, could we sort of expand this to also apply to
non-hospitalized patients? I think that it would be a very
interesting hypothesis to test, and I think there's still a
pretty good rationale for this.


Dr. Torbjørn Omland:


It's interesting that the insoluble group actually showed a
correlation that when the soluble ST2 concentrations and GDF-15.
So there might be that those with more susceptibility to COVID
infections, actually, I thought that, that is actually reflected
by GDF-15 concentrations, but the challenge is how to sort of get
a representative non-hospitalized population, but interestingly,
I was approached by some of the hospital staff that actually are
in contact with general practitioners, and wanted sort of
implement this test also for this group.


Dr. Carolyn Lam:


So Verra, we're really grateful that Allan Jaffe was working with
you in managing this beautiful paper, and if you don't mind me
cheekily paraphrasing that you said you might channel him, if you
could, what would the channeled Allan Jaffe perhaps say about
what's needed in this whole biomarkers fear in COVID-19?


Dr. Vera Bittner:


Hopefully, many. A channeling element is obviously difficult,
because he is such an incredible expert on biomarkers that I
can't even pretend to be able to see, that you might be thinking,
but it seems to me that one thing that we could all agree on is
that it would be really exciting if something like the: get with
the guidelines COVID registry, could decide to measure this
marker perspectively in the participating hospitals, for example.


Dr. Vera Bittner:


Then be able to look at this in a much, much larger population. I
mean, especially with different ethnic backgrounds as well. I
mean, I noticed actually to my surprise that, this Norwegian
study how to fairly high proportion of Asians in the sample, but
that may not be the ethnic distribution that we might see in
different regions of the US, or different regions of the world.
So it would be really nice to incorporate the measurement of this
biomarker in much larger datasets. So things can be explored a
bit further.


Dr. Carolyn Lam:


That's excellent, and Torbjorn, if you could channel Allan. What
would you say?


Dr. Torbjørn Omland:


That's a difficult path, but absolutely just to me what Verra
said. Then I think the importance of prospective studies in the
COVID biomarker field, I think is our at most importance.


Dr. Carolyn Lam:


I think on behalf of both Torbjorn and I, and in fact everyone in
circulation. Thank you, Verra for the amazing work that you and
your team do for circulation as well. Thank you so much for
making the time to share your thoughts today and thank you for
that beautiful, beautiful paper both of you. Thank you.
(singing). Listeners you've been listening to Circulation on the
Run. Thank you for joining us from Greg and I. Don't forget to
tune in again next week.


Dr. Greg Hundley:


This program is copyright, the American Heart Association 2020.