Circulation August 14, 2018 Issue

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 from the National Heart Center and Duke
National University of Singapore. I'm the one you usually hear
chatting about all the papers in your weekly issue, however I am
so delighted to be handing over the mic this week to two beloved
colleagues, and they are Dr Greg Hundley and Dr Vlad Zaha, who
will be taking us through this week's very special issue centered
around cardio-oncology. Here they are.


Dr Greg
Hundley:            
My name is Greg Hundley. I'm a professor at VCU Health Sciences
in Richmond, Virginia. We also have Vlad Zaha, who is an
assistant professor at University of Texas Southwestern in
Dallas.


Dr Vlad
Zaha:                    
Hello, everybody.


Dr Greg
Hundley:            
We're going to be talking about the field of cardio-oncology
today. As we all know, there have been many advances in the
treatment of cancer lately, such that cancer is now becoming in
some regards almost a manageable disease or a chronic disease for
many individuals. But unfortunately we're seeing the emergence of
cardiovascular disease in many patients, so much so that for some
cancers, for example breast cancer survivors, cardiovascular
events have supplanted the occurrence of cancer-related morbidity
and mortality overall.


                                               
And so emerging today is this new field of cardio-oncology, which
is really a bridging discipline between oncologists and
cardiologists that have been focused almost on examining the
relationship between chemotherapies, radiation therapies, newer
targeted immunologic therapies on the development of
cardiovascular events. We as cardiovascular medicine specialists
often become involved and then we are consulted to see a patient
that might be scheduled to receive a cardiotoxic therapy and what
should we do. Maybe they've already received, they're in the
middle of the therapy, and we're asked to provide guidance to
help the patient move through that therapy successfully.


                                               
We're examining survivors now, those that have gone on the
therapy and are experiencing increased cardiovascular risk. And
then finally, a new emerging field that examines the association
of risk factors that seem to be common between cancer and
cardiovascular disease.


                                               
In this issue of Circulation there are theories, really a
miniseries of manuscripts, that are at this interface between
cardiovascular and oncologic science and medicine. Following a
similar miniseries that we published in 2015, this new block of
manuscripts looks on some of the risk factors and mechanisms that
may be common between these disorders.


                                               
We're going to start today and look at this particular issue and
examine the original manuscripts, look at the letters, and then
talk a little bit about the review articles. I will walk through
some of the introduction and then Vlad Zaha, who is working in
cardio-oncology at University of Texas Southwestern, will help
interpret for us some of the results and the meaning.


                                               
The first study, an original manuscript by Simes et. al that's a
subanalysis of the lipid study, and that's the Long-Term
Intervention with Pravastatin in Ischemic Disease. The study is
going to examine the relationship between D-dimer and the future
development of cardiovascular events, but also importantly,
cancer-related events. Remember, D-dimer is the degradation
product of cross-linked fibrin markers of hypercoagulation and
thrombosis. We use this a lot in the emergency department as an
identifier of those at risk when we're suspecting one of CVT,
pulmonary emboli, etc.


                                               
This particular study focused on individuals aged 31 to 75 years
that had experienced previously a myocardial infarction. The
patients were randomized to receive 40 mg of pravastatin versus a
placebo and as part of the study they were followed for six years
to identify cardiovascular events. But at the end of the study
another examination, an extended review, was enabled so that the
patients or participants could be followed for another ten more
years and in addition to looking at cardiovascular events, they
also looked at all-cause mortality and etiologies of that
mortality and specifically cancer.


                                               
Vlad, can you tell us a little bit about some of the results and
what did D-dimer predict?


Dr Vlad
Zaha:                    
D-dimer has been considered a rather non-specific product that
was first introduced in clinical practice in the 1970s for
diagnosis of venous thromboembolisms. It is really interesting in
this study that the others identified D-dimer that it is an
independent predictor of not only long-term risk of arterial and
venous events but all-cause mortality, cardiovascular disease
mortality, cancer incidents and mortality and non-cardiovascular
disease and non-cancer morality.


                                               
It raises interesting questions that are further explored in an
editorial in the same issue about what is a low and what is a
high D-dimer and also what drives the D-dimer generation in these
patients.


Dr Greg
Hundley:            
And so, it's interesting as well that one is identifying those at
risk of cardiovascular disease but also cancer. Do the authors
and the editorialists speculate on what that connection may be?


Dr Vlad
Zaha:                    
The question that is discussed is a common area of etiology that
is being more and more discussed nowadays as bridging the domains
of heart disease and cancer, and that is information. Information
resulting then in alteration of the clotting cascade and
hypercoagulability that may then influence downstream both
atherosclerosis and cancer processes.


Dr Greg
Hundley:            
Very good. It's interesting that we're bringing up this whole
area of thrombosis because that really follows in the next study,
which is a large population cohort assessment that is collected
from a Danish registry of 6600 subjects that had experienced a
lower extremity arterial, not venous, but arterial thrombosis. In
that study what did they uncover, Vlad, in terms of an
association with cancer and previously experiencing a lower
extremity arterial thrombosis?


Dr Vlad
Zaha:                    
Another interesting study where the patients uncovered an
increased risk of cancer compared to the general population,
especially during the first six months before, the investigators
identified an association between lower limb arterial thrombosis
and increased all-cause mortality in common especially for the
smoking-related cancers. This is a very interesting study that
brings up the possibility of opportunistic screening, again
focused on cancer-related signs and symptoms during the
diagnostic workup for lower limb arterial thrombosis.


Dr Greg
Hundley:            
And so, in these first two studies, both large in number, were
identifying issues related to thromboembolic events and
cardiovascular disease that also appear related or associated
with the future development of cancer. The next couple of studies
now switch and address issues related to mechanism. The first is
a relatively large complex translational study by Meijers and
associates that were examining the relationships between heart
and vascular injury and the future development of colon cancer.


                                               
In this particular study there were two separate experiments, one
group performed in mice and the other performed in analyses of
serum and plasma that were collected from human subjects that had
experienced colon cancer. In the first series of experiments in
mice, the mice were induced myocardial infarction and then they
were a strain that were somewhat predisposed to development of
colon cancer. What the investigators did is they examined in this
strain predisposed to the development of colon cancer, the impact
of inducing a myocardial infarction and promoting heart failure
versus those that were not and they identified what looks to be
some sort of association between an increased risk of development
of colon cancer.


                                               
Vlad, what were your observations and thoughts in terms of these
particular findings and results?


Dr Vlad
Zaha:                    
This is an interesting paradigm of bringing basic science
observations and testing them in a translational fashion. It is a
combination of really elegant studies in a mouse model that
identifies potential targets of clinical relevance in a model of
myocardial infarction. The authors evaluate the fact that such
molecules in human cell line models and test the proliferation in
that environment. The question is then: How does this reflect in
a cohort of patients? That, I think, is really the strength of
the study to be able to show that some of the biomarkers
identified which events can have an implication at the bedside.


Dr Greg
Hundley:            
It was really interesting in that in the animals, independent of
the hemodynamic compromise, so the hypotension, the reductions in
EF, these circulating biomarkers that you identified seemed more
associated with the development of colon cancer and then in the
human study, examining similar factors were observed in patients
with colon cancer and heart failure from the circulating blood of
those individuals. Very interesting relationship identified in a
very elegant translational study that involved both animal models
and human subjects.


                                               
The second mechanistic paper is by Li and associates and it's
really addressing the issue of anthracycline-related
cardiovascular injury. Remember, we still utilize anthracycline
chemotherapy today as a fundamental curative component of the
therapeutic regimen for lymphoma, leukemia and sarcoma, also in
those with triple-negative breast cancer as an important
component of that regimen for adjuvant treatment. In this
particular study, the investigators were examining the
implication of phosphoinositide 3-kinase. That is an important
enzymatic regulator of tumorigenesis, but it also when it's
expressed is up-regulated during cardiac stress and really
impacts adverse remodeling and promotion of heart failure.


                                               
In this particular study, the investigators in a mouse model were
looking at blocking this particular enzyme and they had some
really interesting results pertaining to the development of heart
failure and cancer. Vlad, what did you see in this study that
looked unique in that perspective?


Dr Vlad
Zaha:                    
This is an especially interesting study for the perspective of
the oncologists who still have to prescribe anthracycline, given
the uncertainty of early toxicity that can manifest in some
studies in five to ten percent of patients. Also, related to the
late toxicity of anthracycline treatment in survivors of
childhood cancer. What is particularly interesting about this
isoform of phosphoinositide 3-kinase, the gamma isoforms, is that
at the same time blocking this enzyme in macrophages increases
the anti-tumor, I think it's the anthracycline therapy, and
blocking it in the cardiomyocytes, suggests a potential
cardioprotective mechanism.


                                               
Having a target that can be used both to enhance the anti-cancer
effect of anthracycline and to enhance the cardioprotective
mechanism is really a potential ideal intervention that would
help maximize the anti-cancer treatment and at the same time
protect the heart.


Dr Greg
Hundley:            
Fantastic. Again, new research helping to come up with ways for
those that continue to need anthracycline therapy that we may be
able to attenuate some of the untoward cardiovascular effects,
all the while preserving the antagonistic features associated
with the treatment for cancer.


                                               
Let's switch to the other sort of prospective original research
format that we have in Circulation, and that's our letter format.
Remember, our letters are addressing a specific point that can be
readily appreciated in 800 words or less. The first is a letter
by Anquetil et al that examines individuals recorded in the
VigiBase World Health Organization database. This is basically a
database organized around treatment of cancer and cancer
therapeutics and it is examining those individuals that received
sort of a newer class of agents called immune checkpoint
inhibitors. Remember, that is modulation of our immune system to
help attack cancer.


                                               
In some rare circumstances, relatively infrequent, when these
agents have been administered, the immune system has been
unlocked and attacks the heart, promoting a myocarditis that if
not recognized can be fulminant and lead to death. This
particular group identified a new phenomenon that we need to be
aware of and that's just frank myositis.


                                               
Vlad, what are your thoughts on now perhaps these agents being
associated with the development of myositis in the skeletal
muscle?


Dr Vlad
Zaha:                    
Often when adverse events, as you mentioned Greg, are an
important concern for these new powerful tools for the
oncologists and it has been pretty early in the process where
some of the cases have demonstrated severe cardiovascular events.
Fortunately it is a very low percentage, less than 1% of cases
that can manifest with fulminant myocarditis, but this raises
again a question of expanding the view towards other systems when
we are applying one of these early novel molecular interventions.


                                               
In this context, the recognition of myositis in another small
percentage of patients is an important observation and increasing
awareness of both cardiologists and oncologists towards this side
effect is important as not all fatigue is equal and sometimes
that can be due to manifestations of cardiomyopathy and sometimes
it can be a manifestation of oxygen extraction in the peripheral
tissue than muscle contractility. It is an important
hypothesis-generating piece that will allow people to appreciate
more of the complexity of addressing the intrinsic molecular
mechanisms in cancer and heart disease.


Dr Greg
Hundley:            
It sounds that we need to be aware of another potential etiology
of fatigue to put in an armamentarium of differential diagnoses
for those patients that are not getting quite back to where they
were from an exercise and activity level after treatment. The
second research letter focuses on individuals that are receiving
a Fontan procedure. Remember, Fontan procedures are surgical
corrections for those primarily with single ventricles where
we're diverting caval blood to the pulmonary circulation, since
in some situations there's really no functional right ventricle.
These patients over time experience chronic venous hypertension
and have associations with liver disease.


                                               
In this particular research letter, the authors are examining the
relationship between really for the first report in an aggregate
form of the relationship between undergoing a Fontan procedure
and the development of hepatocellular carcinoma. Vlad, any quick
comments to highlight on this particular procedure? I thought
something that was interesting is that these individuals
experienced these hepatocellular carcinomas in their 20s and 30s.


Dr Vlad
Zaha:                    
That's right, Greg. This study confirms observations from
previous case reports and the early occurrence of hepatocellular
carcinoma is raising still important hypotheses for future
clinical trials. On one hand, either there is an increased risk
of hepatocellular carcinoma development in patients with
non-cirrhotic livers after a Fontan operation, or the current
screening modalities using imaging are insufficiently sensitive
to identify early signs of cirrhosis in such patients and this
stratifies them effectively at an early stage in their disease
post-op Fontan procedure.


Dr Greg
Hundley:            
Lastly, let's just briefly discuss here, Vlad, some of the other
editorials and review article formats that we have in
Circulation. A particular one, a perspective that was written by
Peter Libby and Ebert and associates that highlights this
phenomenon potentially implicating inflammation and the link
between cancer and atherosclerotic cardiovascular disease. The
topic of this perspective is really on something called CHIP,
which stands for clonal hematopoiesis of indeterminate potential.


                                               
What is this CHIP? As we age, basically what happens is we
accumulate mutations of hematopoiesis stem cells in our bone
marrow. Over time these little clones, they actually have within
our bone marrow some survival advantages and they can spill out
into the blood and actually can be associated with future
leukemias. Those that have a large population of this particular
clonal progeny, these CHIP-type cells, they have an increased
risk of developing cancer, but also the levels of these are
associated with increased overall mortality and it appears some
risk of cardiovascular disease. How could that be? One
characteristic of this particular cell line is they are
associated with dysregulation of inflammatory genes that go on to
produce, are associated with other inflammatory mediators.


                                               
Vlad, this is calling in question and helping us to examine the
relationship between inflammation, cancer and cardiovascular
disease. What are your thoughts here about these very important
insights provided by Libby and Ebert?


Dr Vlad
Zaha:                    
This is a fascinating perspective, Greg. It really brings, again,
in the offline novel molecular mechanisms that have been
discovered recently and that are becoming a turning point into
the molecular interventions, not only in cancer but potentially
soon in cardiovascular disease prevention and treatment. Having a
common root for a problem set involving such a prevalent
cardiovascular problem as atherosclerosis and cancers reveals the
connection between the different systems and the fact that
integrating our understanding of the molecular regulation of cell
proliferation results in an effective translation of leading to
new targets and new approaches to treat disease.


                                               
It is striking that there are multiple areas where cancer and
inflammation are interacting, one of them being at the cellular
level and other ones at humoral levels, in a way reproducing
other complex mechanisms that we see in regulation of
inter-system interactions within the body.


Dr Greg
Hundley:            
And so, summarizing this entire issue in Circulation, what a
wonderful collection of a series of original manuscripts, both in
the extended and the letter format as well as review articles,
including a primer by Handy and associates that evaluates or
draws attention to our screening tools that how we might examine
the relationship between cardiology and the whole world or
hematologic oncology related issues. And then this very unique
perspective by Peter Libby and really is a continuation of the
growth of this, as we called earlier, the bridging discipline of
cardiovascular medicine and oncology as we work toward improving
survivorship of all individuals with cardiovascular disease and
cancer.


                                               
I want to thank you for the opportunity to be with you today and
encourage you to follow these issues further with the journal.
I'll turn this over to Vlad for any closing remarks.


Dr Vlad
Zaha:                    
Thank you, Greg. This has been a really exciting overview of
important points that are emerging now at this nexus between
cardiology and oncology that give us a broader view of the
complex interactions that the future will materialize for us,
emerging from a molecular intervention on cancer, heart disease,
immunologic disease and probably metabolic endocrinology disease.


                                               
Thank you for listening.


Dr Carolyn
Lam:               
Thank you so much, Vlad and Greg. This is a tremendous issue and
I'm sure, audience, you will be reaching for it right now, I
would.


                                               
Please let all your colleagues know about this podcast and tune
in again next week.