Circulation April 11, 2017 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.


                                               
Today's issue features two exciting papers regarding heart
failure in patients with breast cancer. We will be discussing
this right after these summaries.


                                               
Are we any closer to improving survival in Eisenmenger syndrome?
Well, today's first original paper looks at contemporary trends
and presents a multivariable mortality risk stratification model
based on five simple noninvasive predictors of death in this
population. Dr. Kempny and colleagues from Royal Brompton
Hospital in London in the United Kingdom preform a large
multicenter study in 1098 patients with Eisenmenger syndrome
followed up between years 2000 and 2015.


                                               
At the end of the study almost two-thirds of patients were on
advance therapy for pulmonary arterial hypertension, while only
six patients underwent lung or heart and lung transplantation.
The study showed that despite advances in management, there was
significant mortality amongst contemporary adults with
Eisenmenger syndrome and 25.3% of patients died over a median
follow up period of 3.1 years. Mortality was higher in older
patients, those with a pre-tricuspid shunt, lower oxygen
saturation, absence of sinus rhythm, or with a pericardial
effusion.


                                               
This important study is accompanied by an editorial by Drs.
Lange, from Texas Tech University Health Sciences Center El Paso
and Dr. Brickner from UT Southwest Medical Center in Dallas,
Texas. The editorialists call for a prospective randomized
control trials of the effect of current, or future pulmonary
vasoactive disease targeting therapies on mortality in
Eisenmenger syndrome patients, and say it's time to direct our
efforts from improving risk-stratification towards improving
survival.


                                               
The next study provides experimental evidence of tolerogenic
dendritic cell therapy as a novel anti-remodeling therapy in
myocardial infarction. Tolerogenic dendritic cells are promising,
potent, beneficial regulators of the post-infarct healing process
via their control of T-regulatory cells and M1 M2 macrophages.
Plus they have the advantage of the ease of administration and
feasibility of a heart specific tolero-dendritic cell production.


                                               
In the current paper by co-first authors, Drs. Choo and Lee, and
co-corresponding authors, Drs. Chang and Lim, from Catholic
University Korea and Chai University in Korea, authors generated
tolerogenic dendritic cells by treating bone marrow-derived
dendritic cells with TNF-alpha and cardiac lysate from mice with
myocardial infarction. They then injected myocardial infarction
mice twice with tolerogenic dendritic cells within 24 hours and
at 7 days after LAD ligation. In treated animals, in vivo cardiac
magnetic resonance imaging and ex vivo histology confirm the
beneficial effects on post-infarct LV remodeling. Furthermore,
subcutaneously administered tolerogenic dendritic cells near the
inguinal lymph node migrated to the regional lymph nodes and
induced infarct tissue specific T-regulatory T-cell populations
in the inguinal and mediastinal lymph nodes, spleen, and
infarcted myocardium, all of which elicited an inflammatory to
reparative macrophage shift. The altered immune environment in
the infarcted heart resulted in better wound remodeling,
preserved left ventricular systolic function, and an improved
survival following myocardial infarction. Thus, this study shows
that tolerogenic dendritic cell therapy in a preclinical model of
myocardial infarction may be potentially translatable into an
anti-remodeling therapy for ischemic repair.


                                               
The final paper reports results of cell therapy on exercise
performance and limb perfusion in peripheral artery disease from
the PACE trial, which is an NHLBI-sponsored randomized
double-blind placebo-controlled phase two clinical trial,
designed to assess the safety and efficacy of autologous bone
marrow-derived aldehyde dehydrogenase bright cells in peripheral
artery disease, and to explore associated claudication
physiological mechanisms. In this paper from corresponding author
Dr. Moye from UT School of Public Health in Houston, Texas and
colleagues of the Cardiovascular Cell Therapy Research Network, a
total of 82 patients with claudication and infrainguinal
peripheral artery disease were randomized at nine sites to
receive alcohol dehydrogenase bright cells or placebo. All
patients underwent bone marrow aspiration and isolation of
aldehyde dehydrogenase bright cells followed by 10 injections
into the thigh and calf of the index leg. Results showed that
there were no significant differences in the change over six
months between study groups for the co-primary endpoint of peak
walking time, collateral count, peak hyperemic popliteal flow,
and capillary profusion measured by magnetic resonance imaging.


                                               
Additionally, there were no significant differences for the
secondary endpoints including quality of life measures. There
were no adverse safety outcomes. Interestingly, a post-hoc
exploratory analysis suggested that aldehyde dehydrogenase bright
cell administration might be associated with an increase in the
number of collateral arteries in participants with completely
occluded femoral arteries.


                                               
In summary, cell therapy did not improve peak walk time or
magnetic resonance outcomes, and the changes in peak walk time
were not associated with the anatomic or physiologic MRI
endpoints. However, future peripheral artery disease cell therapy
trial design may be informed by new anatomic and perfusion
insights. These and other issues are discussed in an accompanying
editorial by Drs. Breton-Romero and Hamburg from Boston
University School of Medicine. Well, that wraps it up for our
summaries, now for our feature discussion.


                                               
We are really in the grove here in Washington, D.C. and I am
borrowing the words of my very special, star associate editor,
guest, Dr. Gregory Hundley, and he's from Wakefield University
School of Medicine. We're discussing two very important papers
and they deal with the risk of heart failure following breast
cancer. Why they're so important? Well, first of all, it's about
time we looked at this problem in detail, and secondly, they
actually represent papers in a new section of the journal called
"Bridging Disciplines," and in this case cardio-oncology. Very,
very important topics.


                                               
We're here with the corresponding authors of both papers, Bonnie
Ky from University of Pennsylvania School of Medicine and Dr.
Margaret Redfield from Mayo Clinic.


Dr Gregory Hundley:      Thank you,
Carolyn. I really appreciate that wonderful introduction and also
the chance to talk with Bonnie about this exciting topic.


                                               
So, Bonnie, you've got a paper here, now, where you did a study
in patients with breast cancer, and it sounds like you acquired
echocardiograms over a period of time. Can you tell us a little
bit about that?


Dr Bonnie
Ky:                    
Correct. So this is longitudinal prospective cohort study, it's
an NIH-funded R01, whereby we are enrolling patients from the
breast cancer clinic who are receiving doxorubicin or trastuzumab
or a combination of the two therapies. And we're performing very
careful cardiovascular phenotyping, from the time at which they
initiate chemotherapy through their chemotherapy and then
annually once a year we have them come back, for a total follow
up time of 10 years.


                                               
We took a subcohort, 277 patients, and from their
echocardiograms, we analyze them very carefully for various
measures of left ventricular size, function, not only systolic
function but also diastolic function. We also looked at measures
of contractility such as strain in multiple dimensions, and then
also measures of ventricular arterial coupling, as well as
arterial loads, so how the ventricle interacts with the arterial
system. And what we found was that over a 3.2 period time period,
on population average, these modest declines in left ventricular
ejection fraction, and even across all three treatment groups,
and even at three years there were persistent LVF declines.


Dr Gregory Hundley:      So, I
understand, Bonnie, that you also collected some information as
to whether or not these patients were experiencing symptoms
associated with heart failure. How did the imaging markers relate
to the symptomatology associated with heart failure?


Dr Bonnie
Ky:                    
What we found was that early changes in arterial stiffness or
total arterial load, as well as early changes in EF were
associated with worse heart failure symptoms at one year. A lot
of our other analysis was focused on defining what echo
parameters of remodeling, size, function are driving or
associated most strongly with LVF decline, as well as LVF
recovery.


Dr Gregory Hundley:      And then at two
years, what happened? Did the echo parameters, were they still
associated with heart failure or was there a little discrepancy
there?


Dr Bonnie
Ky:                    
Interestingly, at two years ... no, there was no significant
association with changes in arterial load and heart failure
symptoms at two years.


Dr Gregory Hundley:      So there might
be something transient that's occurring that is associated with
heart failure early, and then the patients still had heart
failure late, so maybe something else is operative. What do you
think we need to do next? What's the next step in your research
and then other investigators around the world; what do we need to
do to design studies to look at these issues further?


Dr Bonnie
Ky:                    
Yeah. What does the field need, the field of cardio-oncology
that's really growing and developing at rapid paces. Some of the
major findings from the study was that changes in total arterial
load were very strongly associated with both LVF decline and LVF
recovery. So total arterial load is the measure of blood pressure
or total arterial stiffness, it's derived from blood pressure.
And to me, that begs the question, or begs the next step is that
changes in blood pressure are associated with decline as well as
recovery. I think, oh, as cardiologists we've also always
recognized the importance of afterload reduction. And to me, this
study suggests that we need a study, a randomized clinical trial,
looking at blood pressure lowering in this population to help
mitigate LVF declines.


Dr Carolyn
Lam:               
I'd actually like to turn it back to you. You are world-renowned
for your work in cardio-oncology. Where do you think this fits
in, and where do you think we need to address most urgently?


Dr Gregory Hundley:      I think where
this fits in wonderfully is a lot of individuals around the world
are collecting echocardiographic measures, and all different
types. And what Bonnie has helped do is clarify what we would
expect to see in this particular patient population. How those
measures change over time and that feeds into another block of
data, when the measurements head south, do we change therapy, do
we add protective agents, and things of that nature. So I think
Bonnie's work really contributes on that front. What she has also
pointed out is that more research needs to be performed, not
necessarily because the patients had heart failure symptomatology
at two years, but not necessarily associated with the decline in
EF; are there other systems in the cardiovascular realm that are
being affected? The vascular system-


Dr Carolyn
Lam:               
Yeah.


Dr Gregory Hundley:      Skeletal
muscle, many other areas. So as cardiologists start to work more
with oncologists in this space, and we're all working together to
make sure that not only patients survive their cancer, but they
have an excellent quality of life, I think we'll see, as we have
in other heart failure syndromes, a look toward other aspects of
the cardiovascular system, body in general, to reduce the overall
morbidity associated with the disease.


                                               
I think what we need to recognize as cardiovascular medicine
specialists is that now for many forms of cancer, cardiovascular
events, and certainly morbidity are becoming the primary issue
that folks have to deal with with survivors. It's not necessarily
the cancer recurrence, it's not necessarily a new cancer, it's
cardiovascular. So we've got to integrate cardiology earlier in
working with oncologists to improve overall survival and create
an excellent quality of life from our different perspectives.


Dr Carolyn
Lam:               
So, Maggie, let's move on to your paper now. You looked at
radiotherapy's effect, whereas Bonnie looked at chemotherapy's
effect. Could you tell us what you did and what you found?


Dr Margaret Redfield:    The rationale for doing
this study was, of course, seeing a lot of patients with HFpEF
who had had radiation therapy for breast cancer, and I always
just sort of assumed that that was because 12% of women over the
age of 40 get breast cancer and 20% of women over the age of 40
get heart failure, but it seemed to be somehow more common than
that. The other rationale was that radiation therapy does not
actually affect the cardiomyocytes; they are very radiation
resistant. And what radiation does is cause microvascular
endothelial cells damage and inflammation, and that is felt to be
fundamental in the pathophysiology for HFpEF.


                                               
So we thought we should look at this. I collaborated with a
radiation oncologist and oncologists, and they were interested in
looking at this because there's a lot of techniques now to reduce
cardiac radiation exposure during radiation therapy, including
proton beam therapy, and they're trying to prioritize who they
use this new technology on. So what we did was start with a
population-based study, all women who lived in Olmsted county who
received radiation therapy for breast cancer in the contemporary
era, where they're already using these dose reducing techniques.
So we wanted to make it relevant to what's going on today. And so
we started with a base cohort of all women. We matched patients'
cases, it was a case-control study, so we matched cases and
controls according to their age at the time of breast cancer,
whether they had heart failure risk factors, like hypertension or
diabetes, whether they got adjuvant chemotherapy, and tumor size,
because we felt it was important that radiation could affect
different parts of the heart, depending on whether it was right-
or left-sided tumor.


                                               
And what we found is that the risk of heart failure increased
with the mean cardiac radiation dose. We measured the mean
cardiac radiation dose in every case and every control from their
CT scans and their radiation plants. And as the radiation dose
went up, the risk of heart failure went up, even matching or
controlling for chemotherapy, which wasn't used that often in
this group, or heart failure risk factors. And the vast majority
of these cases were indeed HFpEF.


                                               
So we then looked at factors that happened in-between the
radiotherapy and the onset of heart failure, making sure that
this all wasn't just coronary artery disease, 'cause we know
radiation can increase the risk of coronary artery disease. And
indeed there were, only in about 18% of cases was there a new
episode of coronary disease in the interim between the
radiotherapy and the breast cancer. So, basically found that the
mean cardiac radiation dose, even in today's era, does increase
the risk of heart failure with preserved ejection fractions.


Dr Carolyn
Lam:               
The things that stuck out to me ... it's population based. You
did such a comprehensive study to really answer very key
questions: dose of radiation, is it really just mediated by age
and age-related risk factors, is it just about MI or could it be
more microvascular disease? Congratulations, I really appreciated
this paper. Some of the take-home messages are directly related
to the treatment of breast cancer, isn't it? And about the
importance of minimizing radiation dose if possible. I suppose
one of the take-homes is, as well, for screening and watching out
for heart failure. One thing though: how were these woman
diagnosed with HEpEF? I mean, this is always the questions I get.
How do you get diagnosed with HEpEF?


Dr Margaret Redfield:    Right, well, first we
started with looking to see if they had a ICD code for heart
failure, and then we looked at each case of heart failure and
determined if they either met Framingham criteria at the time of
the diagnosis and the majority of them did. If they didn't
actually meet the Framingham criteria, we looked to be sure there
was a physician diagnosis of heart failure in the record and that
they had supportive evidence of heart failure: echocardiographic
findings, natriuretic peptide findings, and other clinical
characteristics of heart failure.


                                               
And importantly, in the large control group from where we, you
know, got our controls, people, a very large group of patients
who did not get heart failure, we'd use natural language
processing to look at all those records to make sure we weren't
missing anybody who didn't have an ICD diagnosis or code for
heart failure to make sure we weren't missing any cases of heart
failure. So, we really tried to use very stringent methods to
make sure we had true cases and control groups.


Dr Carolyn
Lam:               
Indeed, and it actually goes back to Bonnie's paper as well,
where we have to remind everyone that the diagnosis of HEpEF
really starts with the symptomatology of heart failure in
particular, that you so rigorously determined. I think just one
last thing, Maggie: what do you think this implies now, for
HEpEF? What do we do in general so the non-radiation-associated,
do we believe more the Walter Paulus-Carsten Tschope hypothesis,
and if so, what do we do?


Dr Margaret Redfield:    Yes, well I think it
really does support that hypothesis. We know that radiation
therapy, again, we know what it does to the coronary
microvascular endothelial cells and that's been elegantly worked
out both in patients and in animal models. I think this really
supports the Paulus hypothesis because this microvascular damage
was able to produce heart failure, so I think that really
supports that hypothesis. And there's been some studies showing
decreased coronary flow reserve in HEpEF patients; it's very
common. So I think indeed it does support that hypothesis and
that the coronary microvasculature is key in the pathophysiology
of HEpEF.


                                               
However it's a little scary to me because that sort of damage,
once it's established, may be very hard to treat. You know,
proangiogenic strategies in peripheral vascular disease have not
yet yielded the benefits that we hoped for, so I think it's a
tough therapeutic challenge that'll be very important to try to
address in pre-clinical studies to try and figure out once the
microvasculature is so damaged how do we treat that? How do we
reverse that process?


Dr Carolyn
Lam:               
Yeah. Words of wisdom. Maggie, thanks so much for inspiring, just
all of us in this field. I just had to say that. You know, you
are the reason that I am totally in love with HEpEF. (laughter)


Dr Margaret Redfield:    (laughter)


Dr Carolyn
Lam:               
So thank you so much for joining me today on the show. In fact,
thank you to all my three guests.


                                               
You've been listening to Circulation on the Run. You must tell
everyone about this episode, it is full of gems.


                                               
Thank you, and tune in next week.