Circulation March 28, 2017 Issue

Caroline:                             
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. Up next, we are discussing
the featured paper in this week's journal regarding the increased
risk of cerebrovascular events in young cancer survivors, the
downside perhaps of surviving cancer, so to speak. But first,
here's your summary of this week's journal.


                                               
The first paper describes the US national trends in atrial
fibrillation hospitalization, readmission, and mortality. This
paper from Dr. Freeman and colleagues of Yale University School
of Medicine in New Haven, Connecticut used data from all Medicare
fee-for-service beneficiaries between 1999 and 2013, and found
that the adjusted rates of hospitalization for atrial
fibrillation increased by almost 1% per year. Median hospital
length of stay remained unchanged at three days, but median
Medicare inpatient expenditure per beneficiary increased from
$2,932 to $4,719 per stay.


                                               
During the same period, the rate of inpatient mortality during
hospitalization for atrial fibrillation decreased by 4% per year,
and the rate of 30-day readmission also decreased by 1% per year,
while the rates of 30-day and one-year mortality decreased more
modestly by 0.5% and 0.26% per year, respectively. Thus, between
1999 and 2013, among Medicare fee-for-service beneficiaries,
rates of hospitalization for atrial fibrillation and the cost of
those inpatient stays increased substantially, but this was
associated with improved outcomes, including lower rates of
readmission and mortality. These findings suggest that increased
hospitalization and more costly contemporary treatments, such as
atrial fibrillation catheter ablation, may be associated with
improved outcomes.


                                               
The next study provides insights into the mechanisms underlying
augmentation of muscle blood flow by ultrasound cavitation of
microbubbles. Now, this is a promising approach for rapidly
correcting tissue profusion in acute ischemic syndromes or for
treating chronic ischemic symptoms. In this paper by first author
Dr. Belsik, corresponding author Dr. Linder, and colleagues from
Night Cardiovascular Institute Oregon Health and Science
University in Portland, Oregon, the authors hypothesized that
pure endergic signaling may be responsible for sheer dependent
increases in muscle profusion during therapeutic ultrasound
cavitation.


                                               
To test this hypothesis, the authors studied unilateral exposure
of the proximal hind limb of mice with and without ischemia
produced by iliac ligation, to therapeutic ultrasound after
intravenous injection of lipid microbubbles. They further
performed a proof of concept study with twelve patients with
stable sickle cell disease. They found that therapeutic
ultrasound cavitation increased muscle profusion by seven-fold in
normal mice, reversed tissue ischemia for up to 24 hours in the
murine model of peripheral artery disease, and doubled muscle
profusion in patients with sickle cell disease.


                                               
Augmentation inflow extended well beyond the region of ultrasound
exposure. Ultrasound cavitation produced a nearly forty-fold
focal and sustained increase in ATP, the source of which included
both endothelial cells and erythrocytes. Inhibitory studies
indicated that ATP was a critical mediator of flow augmentation.
Furthermore, combined indomethacin and inhibition of eNOS abolish
the effects of therapeutic ultrasound, indicating downstream
signaling through both nitric oxide and prostaglandins. Thus, the
authors concluded that therapeutic ultrasounds using microbubble
cavitation to increase muscle profusion relies on sheer dependent
increases in ATP, which can act through a diverse portfolio of
purinergic signaling pathways. Cavitation-related release of ATP
may further serve to explain ultrasound's role in other
therapeutic applications, such as wound and bone healing, and
ultrasound facilitated drug or gene uptake.


                                               
The final original paper describes the age-specific trends of
heart failure in Denmark over the last two decades. Dr.
Christiansen and colleagues of University of Copenhagen in
Denmark studied more that 210,000 Danish individuals over the age
of 18 years, with a first time in-hospital diagnosis of heart
failure from three nation-wide Danish registries.


                                               
They found that the incidents of ischemic and non-ischemic heart
failure in Denmark declined by approximately 50% among older
adults more than 50 years old, but increased by about 50% among
younger individuals, or individuals less than 50 years old,
between 1995 and 2012. Furthermore, they observed a concomitant
increasing trend of various treated co-morbid conditions,
including hypertension, diabetes, and ischemic heart disease in
the population. These findings from Denmark imply a change in the
profile of the heart failure community and portend a higher
burden of heart failure in the future. The increasing trend of
incident heart failure among young individuals especially
warrants further investigation.


                                               
Well, those were the original papers this week. Now, for our
feature discussion.


                                               
Our feature paper today discusses a hugely important modern issue
that may seem like good news at first sight. We know that
survival in cancers has rapidly improved with advances in early
detection and treatment, however the improved survival also
extends the window for the occurrence of long-term complications
such as psycho-social effects, fertility problems, secondary
malignancies, and, as highlighted in today's paper, the risk for
cerebrovascular events. I'm so pleased to have with us first,
author Chloe Bright from University of Birmingham, United
Kingdom, as well as associate editor Dr. Graeme Hankey from
University of Western Australia. Welcome, Chloe and Grim!


Chloe
Bright:                     
Thank you for having me.


Graeme
Hankey:             
Thank you Caroline.


Caroline:                             
Chloe, what an interesting and important focus on cerebrovascular
events following survival from cancer. Please, can you share your
inspiration for looking at this and what you found?


Chloe
Bright:                     
As you've just said, the five year survival rate from teenage and
young adult cancer has been increasing and increasing, and it's
over 80% now, which means there's such a large population of
survivors who are at increased risk, or potentially increased
risk, of developing adverse health outcomes. So, as you know,
cerebrovascular disease can be potentially fatal so it's really
important that we estimate how much teenage and young cancer
survivors are at risk of this. So to start of with our group in
Birmingham actually set up the teenage and young adult cancer
survivor cohort study. And this is a cohort of over 200,000 five
year survivors of cancer who were diagnosed between 15 and 39
years of age. And this was set up because there's hardly any
literature regarding the adverse health outcomes of teenagers and
young adults who have had cancer.


                                               
So, as I said, cerebrovascular disease is a really important
outcome to look at. So we decided we've got this resource in the
UK, which is the Hospital Episode Statistics, and this carries
information on all the inpatient hospitalizations in England. So
from this we were able to determine how many people with teenage
and young adult cancer had been hospitalized for cerebrovascular
events and compare this to what we would expect to see in the
general population to see if they had an increased risk or not.
So from limited previous literature that was out there we did
know that TYA cancer survivors had an increased risk of
developing a cerebrovascular event. However, we were unsure how
this risk varied with certain explanatory factors, such as age of
cancer diagnosis or the decade of cancer diagnosis, gender, and
attained age, so that's the age at which a stroke event might
occur. So the main aim of our study was to quantify this.


Caroline:                             
Yes and to put some numbers to that increased risk. It was a 40%
increased risk, wasn't it? That is striking.


Chloe
Bright:                     
We observed almost 2,800 cerebrovascular events. That related to
a 40% increased risk of being hospitalized compared to what we
would expect to see in the general population, which is really
quite substantial.


Caroline:                             
Now, were there particular risk factors that were associated with
more cerebrovascular complications like certain types of tumors
or certain types of therapies and so on?


Chloe
Bright:                     
Survivors of central nervous system tumors, head and neck tumors,
and leukemia were all at the greatest risk compared to the
general population. And this is probably related to radiotherapy
that they had for their initial treatment. So radiotherapy to the
neck, which could involve damage to the carotid artery, or
radiation to the head which again could cause damage to the
cerebral arteries in the brain. And then also we found that the
risk increased dramatically as people aged for neck tumor
survivors and CNS tumor survivors. So specifically cerebral
infarctions, the additional number that we saw was a lot greater
in, say, survivors over age 60. And this is probably because this
is when strokes in the general population are becoming more
incident.


                                               
And actually an interesting finding, we observed that males
actually had a higher number of excess infarctions than females,
and this was especially among head and neck tumor survivors. So
we can't confirm this, but this could potentially be due to
difference in smoking habits because there could be a said
etiology between smoking and the risk of head neck cancer and
also smoking and the risk of stroke. Unfortunately, we didn't
have the information on smoking status to confirm this.


Caroline:                             
This is a huge study. It shows a substantial increased risk of
stroke in these young cancer survivors, and also sheds light on
the possible underlying mechanisms. What you mention about
vasculopathy following radiotherapy really reminds me about what
we learn about breast cancer radiotherapy and the risk of
myocardial infarction.


                                               
Graeme, what are your perspectives on this paper please?


Graeme
Hankey:             
Well as an editor, as everyone knows, what we're really looking
for are four main points. Firstly that the study was ethical,
which it was. Secondly that the results are valid, internally and
also externally. And we're very confident in the validity of the
results. This was a very large study of 180,000 people, and more
importantly had 2,800 cerebrovascular events so that's a lot of
[inaudible 00:12:25] and the followup was pretty rigorous over 11
years, and the outcome events were [inaudible 00:12:32] by a data
linkage through the hospitalization for the cerebrovascular
events.


                                               
The other two key features of course is are the results novel and
are they important? And these are novel results. There's only
been one previous similar study of a Danish cohort that was only
43,000 but one quarter the size of this study, and one year
survivors of teenage and young adult cancer from 1943 to 2009 and
followed up. And the results were actually very similar, showing
a 1.3 or 30% increased risk of hospitalization for
cerebrovascular events. Again supporting the validity of this
recent study to obtain similar results, but in a four times
greater population and in a more contemporary population whose
patients were recruited between 1971 and 2006 and followed up
from 1997 to 2012.


                                               
And the other thing is it's not just ethical, valid, and novel,
but it's important because it really has big implications for
stroke prevention in young adult survivors of cancer. And it has
implications for once they get the diagnosis and they're through
their treatment to really focus on what were their pre-morbid
vascular risk factors? Are they actually causal risk factors and
not just cancer but also for future stroke like smoking and
alcohol, and hypertension and diabetes? Secondly to try and
recognize what is their absolute risk? Are they men who are at
higher risk? Have they had previous irradiation that probably
puts them at higher risk, as well as their current respective
profile?


                                               
Thirdly for them to then realize what's the impact of their
cancer diagnosis on their future behaviors if they become
depressed or change their diet or taking other treatments, or
abusing drugs, and could that increase their vascular risk? And
fourthly, what should be done? Should they just control their
vascular risk factors through lifestyle? Or should we actually
have a randomized trial of risk factor control, and/or
antiplatelet therapy and/or statins and/or blood pressure
lowering in these high risk survivors of cancer who are sill in
their forties or fifties. Should they actually be taking
antiplatelet therapy or statins? We probably need a randomized
trial because they're high risk, we would think, or certainly a
sub-population.


Caroline:                             
Thanks Graeme for framing that so excellently. You're absolutely
right that these are the things we look for in a paper as
editors. And for our listeners to hear that is just so important.


                                               
Well, I'd like to hand it over to you now Chloe. What are the
next steps in your mind? What are the remaining gaps in knowledge
you'd like to address?


Chloe
Bright:                     
I really think it relates to what Graeme just said. We need to
get the information on the specific radiotherapy, the doses that
have been used, the potential lifestyle factors of these
individuals to see how much of an effect that has on the risk of
stroke. So potentially conduct a case control study while we're
able to get this information and then use that. And then, as
Graeme said, once there is more information potentially a
randomized control trial might be useful. But again, I think we
need some more information before we can get the go ahead to
doing that.


Caroline:                             
Great. Just one more quick question please. You know, Chloe, you
found that those who were more recently treated had a higher risk
of cerebral hemorrhage than among survivors diagnosed earlier.
Now, did you have any postulations on why this was the case?


Chloe
Bright:                     
This increase in the hemorrhage with more recent diagnosis was
actually restricted to glial tumor survivors. So one explanation
that we thought might explain this was that in recent years due
to advances in treatments those glial tumor survivors, glial
tumors who had more advanced stage at diagnosis, potentially
surviving a little bit longer, so reaching five year survival
which would enter them into our study. However they potentially
might be having another occurrence, which would be causing them
to have a hemorrhage, which in the previous decades perhaps they
wouldn't have survived that long in the first place. That's just
one of many ideas.


Graeme
Hankey:             
I think the recurrence of not just glioma but perhaps also
melanoma that the survival is much greater now with new
immunomodulating therapies for melanoma, we'll probably see
longer survival in melanoma which typically when it metastasizes
is hemorrhagic and perhaps also leukemia with thrombocytopenia,
with more hemorrhage and other metathesis. The other thing it
could be though is a diagnostic ascertainment bias in that I'm 60
now, and when I started neurology 35 years ago we didn't really
have much brain imaging and couldn't diagnose intracerebral
hemorrhage very well. And clinical diagnosis wasn't very
reliable. Now the imaging which can actually distinguish
hemorrhagic from ischemic stroke is much more widely available.
And I suspect there's a greater increase in the diagnosis of
cerebral hemorrhage now because of better imaging. We've seen
that in other epidemiologic studies with that diagnostic trend.


Caroline:                             
What excellent points. Thank you so much Chloe and Graeme.


                                               
Well you've been listening to Circulation on the Run. Thanks for
joining us today and don't forget to tune in next week.