Circulation August 18, 2020 Issue

This week’s episode of Circulation on the Run features author Ami
Aronheim and Associate Editor Thomas Eschenhagen as they discuss
early cardiac remodeling that promotes tumor growth and
metastasis.


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


Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor and
director of the Pauley Heart Center at VCU Health in Richmond,
Virginia.


Dr Carolyn Lam: Greg, today we're taking a look at the
cardio-oncology world in our feature discussion, but in a very
interesting reverse way. Cardio-oncology, what would you think
of? I suppose the effects on the heart of cardiotoxic drugs that
we use in oncology, right? But this feature paper looks at it the
other way around and says does the heart and its remodeling
promote tumor growth and cancer? Terribly interesting data coming
right up after we discuss a couple of papers, well, all the
papers in today's issue.


So I want to start. Greg, do you remember what parasites are and
why they're important?


Dr Greg Hundley: Well, Carolyn, this is actually one of the
things that I do remember because we study the parasites when
we're looking at microcirculatory dysfunction after the
administration of potentially cardiotoxic agents for treatment of
cancer. But how about you tell us a little bit more.


Dr Carolyn Lam: This is going to be very basic just for all of
us. Now, the blood vessels are composed of endothelial cells and
mural cells. Endothelial cells line the vascular lumen. Whereas
the mural cells, which include faster smooth muscle cells and
parasites adhere to the abluminal surface of the endothelium.
Parasites regulate vessels stabilization and function, and their
loss has been associated in diseases such as diabetic
retinopathy, vascular malformation, stroke, and cancer. Just like
you said, Greg.


Now here we have a series of elegant experiments by Dr Mariona
Graupera from IDIBELL in Barcelona and colleagues who use genetic
mouse models to identify the specific molecular signature of
mural cells at early and late stages of the energetic process and
unveil their biological relevance. Their results show that
phosphatidyl inositol 3-kinase or PI3K-beta is the main regulator
of parasite, proliferation and maturation in vessel growth.
PI3K-beta deletion in parasites triggered early parasite
maturation, whereas exacerbated PI3K signaling delayed parasite
maturation, and thus vessel maturation during angiogenesis.


Dr Greg Hundley: So clinically what's the take home message here.


Dr Carolyn Lam: The proposed model of mural cell maturation
together with the tools developed would be instrumental for the
characterization of mural cells in pathologies associated with
deregulated vessel growth, such as ischemia stroke, vascular
malformation, diabetic retinopathy, and cancer. The therapeutic
potential of modulating parasite biology through PI3K signaling
provides a new window of clinical intervention for vascular
related diseases in which parasite dysfunction contributes to
their onset and or progression.


Dr Greg Hundley: Very nice, a very important cell type Carolyn.
Well, my paper comes from Professor Xiang Qian Lao from The
Chinese University of Hong Kong. In this paper, the authors
investigated in 140,072 adults all greater than the age of 18,
without hypertension who joined a standard medical screening
program with 360,905 medical exams that occurred between the
years of 2001 and 2016. They assess the joint associations of
habitual physical activity and long-term exposure to find
particulate matter with the development of hypertension in
Taiwan.


Dr Carolyn Lam: Wow. A huge study. So what did they find Greg?


Dr Greg Hundley: After adjusting for a wide range of co-variants
including a mutual adjustment for physical activity or
particulate matter, a higher physical activity level was
associated with a lower risk of hypertension. Whereas a higher
level of particulate matter was associated with a higher risk of
hypertension. No significant interaction was observed between
physical activity and particulate matter.


So Carolyn in conclusion, a high physical activity and a low
particulate matter exposure were associated with a lower risk of
hypertension. What we would expect the negative association
between physical activity and hypertension remain stable in
people exposed to various levels of particulate matter. The
positive association between particulate matter and hypertension
was not modified by physical activity. Thus, Carolyn the authors
believed their results indicate that physical activity is a
suitable hypertension prevention strategy for people residing in
relatively polluted regions.


Dr Carolyn Lam: Oh, thanks for summarizing that. So well, Greg,
Hey, I've got a question for you. Do you measure a high density,
lipoprotein cholesterol or HDL cholesterol? Do you measure the
levels or do you measure the particle concentration in your
clinical practice?


Dr Greg Hundley: I think just the levels Carolyn.


Dr Carolyn Lam: Yeah. Same, but there's a lot of data coming out
about the particle concentration. Let's review a little bit about
that. So the HDL cholesterol is an established athero-protective
marker, particularly for coronary artery disease, but HDL
particle concentration may better predict the risk. However, the
associations of HDL cholesterol and HDL particle concentration
with ischemic stroke and with myocardial infarction among women
and blacks has not been well defined. And so Dr Rohatgi from UT
Southwestern and colleagues analyzed individual level participant
data in a pool cohort of four large population studies without
baseline atherosclerotic cardiovascular disease. These were the
Dallas Heart Study, the ERIC study and the MISA study, as well as
the PREVENT study.


Dr Greg Hundley: What did they find? Were there any unique pieces
of data related to either sex or those of black race?


Dr Carolyn Lam: They found that HDL particle concentration is
inversely associated with the specific endpoint of ischemic
stroke overall and among women. Whereas HDL cholesterol was not
associated with ischemic stroke. Neither HDL particle
concentration nor HDL cholesterol levels were associated with
myocardial infarction in blacks. Thus HDL particle concentration,
but not HDL cholesterol may be a useful risk marker for ischemic
stroke. HDL particle concentration may be a useful risk marker
for both myocardial infarction and ischemic stroke among women.
There is likely minimal utility of HDL markers for risk
prediction of myocardial infarction in the black population.


Dr Greg Hundley: Thanks Carolyn. That was such a great
introduction and overview and then the results was so clear.
Carolyn, my next paper comes from Dr Peter Willeit from the
Medical University of Innsbrook. In this paper, the author
systematically collated carotid intima-medial thickness data from
randomized controlled trials. The primary outcome was a combined
cardiovascular disease endpoint defined as myocardial infarction,
stroke, revascularization procedures, or a fatal cardiovascular
event. The authors estimated intervention effects on carotid
intima-medial thickness progression and incident CVD for each
trial before relating the two using a Bayesian eta- regression
approach.


Dr Carolyn Lam: Oh, this is important. So what did they find?


Dr Greg Hundley: Carolyn, they're going to have 10 micrometer per
year evaluations. So across all intervention, each 10 micrometer
per year reduction of carotid intima-medial thickness progression
resulted in a relative risk for cardiovascular disease of 0.91
with an additional relative risk for cardiovascular disease of
0.92 being achieved independent of carotid intima-medial
thickness progression. So combining these results, the authors
estimate that interventions reducing carotid intima-medial
thickness progression by 10, 20, 30 or 40 micrometers per year
would yield relative risks of 0.84, 0.76, 0.69 or 0.63 each
incrementing with the magnitude of reduction in micrometers per
year. Results were similar when grouping trials by type of
intervention. Time of conduct, time to ultrasound follow-up,
availability of individual participant data, primary versus
secondary prevention trials, the type of carotid intima-medial
thickness measurement, and the proportion of women in the
studies.


Dr Carolyn Lam: So could you summarize that Greg?


Dr Greg Hundley: You bet, Carolyn. So the extent of intervention
effects on carotid intimal-medial thickness progression predicted
the degree of cardiovascular disease risk reduction. This
provides a missing link supporting the usefulness of carotid
intimal-medial thickness progression as a surrogate marker for
cardiovascular disease risk prediction in clinical trials.


Dr Carolyn Lam: Indeed. Thanks, Greg. It's important because it
also quantifies that risk reduction. Very nice. Now let's just
round up with some other papers in the issue. There is a
perspective paper by Dr Bunch on Dementia and atrial
fibrillation, a research letter by Dr Ellinor on myocyte specific
upregulation of ACE two in cardiovascular disease, the
implications for our SARS-coronavirus to mediated myocarditis.
There are letters to the editor regarding the article small extra
cellular macrovesicles mediated, pathological communications
between dysfunctional adipocytes and cardiomyocytes as a novel
mechanism, exacerbating ischemia reperfusion injury in diabetic
mice. These letters were by Dr Li with response by Dr Ma. There's
a research letter by Dr Natarajan on genetic variation and
cardiometabolic traits and medication targets and the risk of
hypertensive disorders of pregnancy.


Dr Greg Hundley: Carolyn, I've got a couple other features to
describe. Aaron Baggish and Ben Levine provide an On My Mind
piece, related to sports after COVID-19. Jeffrey Smietana has an
ECG challenge regarding an ELVAD artifact. Then finally, Bridget
Kuhn has cardiology news related to an announcement from the
Association of Black Cardiologists calling for an urgent effort
to address health inequality and diversity in cardiology. Can't
wait to get to that feature discussion and that really unique
twist in cardio-oncology.


Dr Carolyn Lam: Here we go. Greg.


Based feature discussion. We are diving into the world of
cardio-oncology. Now, usually that refers to the intersection
between cancer and cardiovascular disease, where we usually talk
about cancer and cancer treatment effects on the cardiovascular
system. But emerging data now suggests the concept of reverse
cardio-oncology, whereby heart disease potentiates cancer.
Today's feature paper really provides very important and
significant preclinical data to support this. I'm so pleased to
have with us, the corresponding author, Dr Ami Aronheim from
Israel Institute of Technology, as well as our associate editor,
Dr Thomas Eschenhagen from University Hospital Hamburg Eppendorf
in Germany. Ami, thank you very much for joining us today.
Please. Could you walk us through your very elegance study and
the results?


Prof Ami Aronheim: We used a model, which is called the
transfers, all the constriction, which promotes pressure overload
on the heart. Actually following this procedure, we implanted
cancer cells into mice and we followed the growth of these
tumors. Actually we found out that the tumors of a tuck operated
mice is growing much faster. Also when we used a metastatic
model, namely, when we injected cells into the tail vein, we
obtained more metastatic lesions in the lungs. Actually we found
out that the serum from these mice is able to promote the
variation of cancer cells in vitro. Then we also identified a
protein, which is potentially promoting these cell proliferation
in vitro.


Dr Carolyn Lam: That is really significant. I mean, am I right
that this is the first study to show that cardiac remodeling
actually promotes tumor growth and metastasis and this is
probably via secreted factor.


Prof Ami Aronheim: This is the first paper showing that early
events of cardiac remodeling promote cancer cell proliferation.
It is known that heart failure by the work of De Boer’s group,
that heart failure is promoting cancer load in mice. This paper
was also published in Circulation 2018.


Dr Carolyn Lam: Indeed. Thank you for reminding me about that.
And I am a huge fan of Rudolph de Boer and his work. Indeed.
Could I ask though, in your study, did you identify a particular
secreted factor?


Prof Ami Aronheim: We looked at the RNA seq from conduct
remodeled heart, and we looked for secreted factors in the heart
and we focused on two secreted factors CTGF and periostin, which
are known to promote cancer growth. And indeed we found in our
mice models that reduced in level is increased in the serum of
mice of tuck operated mice. Once we deplete the serum from
periostin, we ambulated this increase in cell proliferation.


Dr Carolyn Lam: Wow. So periostin appears a culprit, but I'm sure
the listeners are dying to know. Was there any human data that
you had that supported the animal findings?


Prof Ami Aronheim: The model in mice, the tack operation, it's
hard to find the right model in human because the operation is
really rapid. When the mice wake up, they have this pressure
overload, the only disease which in human correlates or is
mimicked by the tag is Altucher's stenosis, which is the
restriction of the outtake evolve, the right aortic valve]. And
we looked in these patients and what we found out, we looked at
the echo cardiography data of a lot of patients. We actually
found out that for young basically patients 40 to 60 years old,
if they have moderate to severe aortic stenosis, they have higher
risk to develop cancer about 1.6-fold higher than our external
these patients. Although I must say with caution that this size
group is quite small and it should be repeated with much higher
number of patients.


Dr Carolyn Lam: Wow. Thank you so much, Ami. Thomas, I have to
bring you in here. Thank you for managing this very remarkable
paper. Could you share some thoughts on what you think this means
for the field?


Thomas Eschenhagen: We all immediately as editorial team like
this paper. When it came in on the background of the different
paper, it really provides significant additional evidence that
this interaction between cancer and the heart is two sided. And
that's, as you said in the intro, that's really very important.
And it's all very interesting that apparently these two different
models used by Rudolf de Boer, which wasn't ischemia myocardial
injury model. And here it's a hypertrophy model with early
remodeling. They both do similar things, but apparently by
different mechanisms. Because the number of the factors
identified in the de Boer paper do not match with, with these two
factors, CTGF and periostin. And for both, I think we have now
convincing evidence that they may play a role, but it also shows
that this is probably a quite complex interaction between the
heart and the cancer. That makes it extremely interesting.


Of course it's important because it's such a common comorbidity,
I mean, cancer, cardiovascular diseases, are the most prevalent
and the second most prevalent diseases is cancer. So this
interaction must be very, very important. And it's very good that
these two papers now focus of you on the reverse side and not
only on the classic cardiac toxicity side, which me as
pharmacologists, of course, we, I was always interested in.


Dr Carolyn Lam: Yeah, indeed. I mean, Thomas me too. As a heart
failure clinical trial list and epidemiologists, if I may, I
always thought it was just shared risk factors, you know, age
being particularly one of them.


Thomas Eschenhagen:   Obviously, as you said, shared
risk factors do play a role must, must their role. So it's
certainly not only this direct interaction, but this new paper
shows that there is in addition to this risk factor model,
something specific. And that of course could be, I mean, at least
theoretically be addressed.


Dr Carolyn Lam: For both Thomas and Ami, what do you think are
the implications now? I mean, should we be screening all patients
with aortic stenosis more closely for cancers? What do you think
are the clinical implications? Maybe Ami first?


Prof Ami Aronheim: I think cardiovascular disease patients are
already watched very carefully beforehand. But certainly I think
that they should be also observed for cancer specifically. So yes
I believe it should be. Also I this cardiovascular treatment
should consider to make them early as possible to avoid any
interaction with cancer.


Dr Carolyn Lam: Yeah, that completely opens the field to, for
example. Early aortic valve replacement, reducing subsequent
cancer risk, like you mentioned in your paper, I mean, that's
just mind blowing. Thomas, what do you think?


Thomas Eschenhagen: I agree, 10 years ago, we said that more
cancer patients, particularly those under treatment should be
sent to the cardiologist to look for the heart. Now we will say
the other way around as well. We really need to look more
carefully for cancer. So I think this paper and the other one
have the consequences we should do more here. There's also
obviously a number of very interesting questions because one of
the findings I found fascinating in this paper by Ami and this
group was that this mouse strain, which finally did not show the
classical science of remodeling after transverse aortic
striction. So no BNP, no NP, no BDMEC increase in this small
strain. There was no increase in cancer growth.


Very interesting, because normally you would think somehow that
these mice, which were kind of normal in the cardiac response
would be worse, but in this respect they were better. So that's a
very interesting aspect. The second aspect I found really
fascinating is the human data suggest, I guess it's quite
preliminary data, but there's a suggestion here that this
interaction is mainly seen in younger patients. And I'm not quite
sure what that means, but it's something to look at.


Dr Carolyn Lam: Wow. Thanks for highlighting those Thomas. So Ami
maybe the last word from you. Given all of this remaining
questions and so on, what are your next steps?


Prof Ami Aronheim: First, I wanted to comment something more wide
view for this interaction that we find with cancer. I think all
the organs actually communicate with one another. The fact that
we are looking on a heart and cancer, this is due to the fact
that it's easy. We have the models working in the lab and it's
easy. But I'm sure if we're going to look to other diseases and
other organs, there will be other connections of the heart with
other organs and other diseases and maladies, which by conducting
modeling, they will promote or maybe even reverse other maladies.
So I'm sure that there is a communication between all organs,
many organs altogether, and they will affect one another.


Our directions currently are to look more precisely for the
periostin story because we follow this mainly in vitro and would
like to follow it in vivo. Also I think this mice model are nice,
but to look also in human, where the periostin in aortic stenosis
patients, where then, we can find out earliest in, in the serum
before intervention, and to look after whether this secreted
factor goes down or reduced. Also we are looking in other
transgenic model that we generated along the years, which are
known to result in cardiac modeling. We want to see whether these
mechanisms are similar or different and whether they can promote
also cancer progression. The use of these transgenic mice is very
nice because we can induce them and we can shut down them so we
can learn more about the kinetic, which influence one another,
and exactly whether they can be reversed or not.


Dr Carolyn Lam: Thank you so much Ami for sharing your thoughts
on those future actions, a lot of work and such worthwhile areas
to explore. Thank you too, Thomas for sharing your thoughts.


Listeners. Thank you for joining us today on circulation on the
run.


Dr Greg Hundley: This program is copyright the American Heart
Association, 2020.