Circulation December 19/26, 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.


                                               
This week's journal features two papers. One a research letter
and the second an original article, both focusing on the effect
of ionizing radiation on interventional cardiologists. I'm sure
that cuts close to the heart, so please stay tuned. Coming up
right after these summaries.


                                               
The first two original articles in this week's journal describe a
metabolic adaptation that is good for the abnormal cell but bad
for the patient. This is a shift in glucose metabolism called the
Warburg phenomenon where there is failure of two fundamental
pathways. Number one glucose metabolism and number two
mitochondrial oxygen sensing. This Warburg phenomenon enables a
reliance on glycolysis despite an abundance of available oxygen.
These two circulation articles uncover new players in the Warburg
phenomenon, both in the setting of pulmonary arterial
hypertension. One in the pulmonary arterial endothelial cells,
and the second in fibroblasts.


                                               
In the first paper, first and corresponding author Dr. Caruso and
co-corresponding author Dr. Morrell from the University of
Cambridge examined the microRNA and proteomic profiles of blood
outgrowth endothelial cells from patients with heritable
pulmonary arterial hypertension due to mutations in the bone
morphogenetic protein receptor type two, or BMPR2 gene, and in
patients with idiopathic pulmonary arterial hypertension. They
demonstrated that reduced expression of microRNA-124 in pulmonary
arterial hypertension endothelial cells was responsible for the
dysregulation of the splicing factor polypyrimidine tract binding
protein 1, and its target pyruvate kinase M2 or PKM2, which is a
major regulator of glycolysis and which contributes to abnormal
cell proliferation. Reduced BMPR2 levels were associated with
reduced microRNA-124 expression.


                                               
In the second paper first author Dr. Zhang, corresponding author
Dr Stenmark and colleagues from the University of Colorado
studied pulmonary adventitial fibroblasts isolated from cows and
humans with severe pulmonary hypertension. PKM2 inhibition
reversed the glycolytic status of pulmonary hypertension
fibroblasts, decreased their cell proliferation and attenuated
macrophage interleukin beta expression.


                                               
Normalizing the PKM2 to M1 ratio in pulmonary hypertension
fibroblasts by using microRNA-124 over expression, or by PTBP1
knockdown, reversed the glycolytic phenotype, rescued
mitochondrial reprogramming and decreased cell proliferation.
Finally, pharmacological manipulation of PKM2 activity or
treatment with histone deacetylase inhibitors produced similar
results. These findings provide new avenues for the treatment of
pulmonary arterial hypertension and are discussed in an
accompanying editorial by Stephen Archer from Queen's University
in Ontario Canada.


                                               
The next paper tells us that the addition of ezetimibe to
simvastatin in patients stabilized after acute coronary syndrome
reduces the frequency of ischemic stroke, with a particularly
large effect seen in patients with a prior stroke. First and
corresponding author Dr. Bohula and colleagues from the TIMI
study group investigated the efficacy of the addition of
ezetimibe to simvastatin for prevention of stroke in the
IMPROVE-IT trial where post ACS patients were randomized to
placebo and simvastatin or ezetimibe and simvastatin and followed
for a median of six years.


                                               
The current study focused on patients with a history of stroke
prior to randomization. The authors found that the addition of
ezetimibe to simvastatin reduced the frequency of ischemic stroke
with a hazards ratio of 0.79, with a particularly large effect
seen in patients with a prior stroke, where the hazards ratio was
0.52, compared to patients without a prior stroke where the
hazards ratio was 0.84. Hemorrhagic strokes were rare and a non
significant increase in hemorrhagic stroke was observed with the
addition of ezetimibe. Thus, the authors concluded that it is
reasonable to consider the addition of ezetimibe, a generic lipid
lowering therapy with an acceptable safety profile, to a moderate
to high intensity statin regimen for the prevention of ischemic
stroke in patients with established ischemic heart disease, with
or without a prior stroke.


                                               
Atrial fibrillation is the most common sustained arrhythmia in
hypertrophic cardiomyopathy, but the influence of atrial
fibrillation on clinical course and outcomes in hypertrophic
cardiomyopathy had remained incompletely resolved. That is until
today's paper in circulation. First and corresponding author Dr.
Rowin and colleagues from Tufts Medical Center accessed the
records of 1,558 consecutive patients followed at the Tufts
Medical Center hypertrophic cardiomyopathy institute for an
average of 4.8 years from 2004 to 2014.


                                               
20% of patients had episodes of atrial fibrillation, of which 74%
were confined to symptomatic paroxysmal atrial fibrillation,
while 26% developed permanent atrial fibrillation. They found
that the timing and frequency of paroxysmal atrial fibrillation
events were unpredictable with an average two year interval
between the first and second symptomatic episodes but progressing
to permanent atrial fibrillation uncommonly. They further found
that atrial fibrillation was not a major contributor to heart
failure morbidity, nor a cause of arrhythmic sudden death, and
when atrial fibrillation was treated it was associated with low
disease related mortality, no different than for patients without
atrial fibrillation. Finally, atrial fibrillation was an uncommon
primary cause of death in hypertrophic cardiomyopathy, but this
was virtually limited to embolic stroke, thus supporting a low
threshold for initiating anticoagulation therapy.


                                               
That warps it up for our summaries. Now for our feature
discussion. This week's journal carries two papers that refer to
the health risks of ionizing radiation to interventional
cardiologists. Yes, you heard me right. You're going to want to
listen up. These are going to send chills up our spine, or rather
maybe chills into our brains and into our blood according to the
papers.


                                               
To discuss these two papers I have with us associate editor from
UT Southwestern, Dr. Manos Brilakis, as well as the corresponding
author of the first paper Dr. Maria Andreassi from CNR Institute
of Clinical Physiology from Pisa Italy. Maria, could you start us
off by telling us what you found in your research letter?


Dr Maria Andreassi:        In
our study we evaluated the circulating microRNA profile in
interventional cardiologists in order to provide insights into
the molecular and the biological situation and the underlying
association between occupational low dose radiation exposure in
cath lab and the potential long term disease risk. The hypothesis
of our study was based on the evidence that the microRNAs are
crucial regulators of gene expression. And they have been shown
to be dysregulated in many human disease. Moreover, the stability
and the tissue selectivity of circulating microRNAs make them
ideal biomarkers to explore disease potential clinical disease
risk.


                                               
In summary, our findings exhibited the dysregulation and the down
regulation of acute specific circulating microRNA, the brain
specific microRNA-154 and the microRNA-2392. This tells us
significantly involved in the deregulation of the three brain
pathways and the brain cancer pathway as demonstrated by
systematic analysis. In particular, the dysregulated labels so
the brain specific microRNA-154 in interventional cardiologists
support the notion that the brain damage is one of the main
potential long term risk on unprotected head radiation in
interventional cardiologists with possible long lasting
consequences on the cognitive function.


Dr Carolyn
Lam:               
That is really striking. Brain specific microRNA was shown to be
dysregulated in interventional cardiologists compared to controls
who were not exposed to radiation. As I understand it, these
dysregulated microRNAs can be seen in certain forms of epilepsy
and Alzheimer's disease and certain brain cancers and so the
concern is very obvious for those of us who are interventional
cardiologists. But your study did not actually relate these two
specific adverse events. Is that correct?


Dr Maria Andreassi:       
You're right. Yes. microRNA-154 was first identified as a brain
specific microRNA which is involved with inner synapse
development and the directly implicated in [inaudible 00:12:15]
and memory. Additionally, decreased expression of this microRNA
class, was previously reported in several brain disorders
including the thymus disease and bipolar disorder. This microRNA
has also been shown to be down regulated in several brain cancers
such as neuroblastomas. The reduced expression of the
microRNA-154 is a predictor of progression and prognosis of human
gliomas. This data strongly support it's important role in brain
tumors. Our findings are of particular interest in relation the
handle exposure to the pathology of the head, the [inaudible
00:13:13] 20, 50 millisieverts. The equivalent to 1,000, 2,000
chest x-rays and can reach a lifetime cumulative exposure around
two sieverts for left hippocampus and one sievert for right
hippocampus.


Dr Carolyn
Lam:               
That really makes me go, yikes. But Manos, as an interventional
cardiologist yourself, what are your thoughts? And also your
thoughts please on that other paper that's in this week's
journal?


Dr Manos
Brilakis:           
First of all, let me just congratulate Maria Andreassi, she's
been one of the leaders in this area and published several papers
and this is one of them. It's really important to have these
studies because unfortunately we as interventional cardiologists
tend to forget about the negative affects of radiation because as
you hear, people don't really see them and this can happen many
years down the line. And by the time they happen, it's too late.
It's really useful to have the studies to bring our attention the
importance of keeping the radiation exposure to the patient and
to ourselves as low as possible.


                                               
The other paper in addition to the one just discussed, is a paper
that looks at DNA damage on operators performing endovascular
aortic repair. As a preface, these are procedures demonstrated
the aortic aneurism repairs which are very intense radiation
wise. They are long procedures, fielding can sometimes be
challenging for the operator. There is significant exposure of
the operator to x-ray. What they did is they measured some
markers of DNA damage and repair. Specifically gamma-H1AX and
DDR, the DNA damage response marker and the pATM. They measured
them in circulating lymphocytes in operators who performed the
endovascular aortic aneurism. What they found is that there were
significantly higher levels of those markers immediately after
those operators performed those procedures. And they did the same
thing after x-ray using leg shielding.


                                               
That's a very good reminder for us that the x-ray tube actually
is not on the top of the table, but the x-ray tube, the
generator, of the x-rays is actually on the bottom. Then the
x-ray goes through the patient and the detector is at the top of
the table and what happens is the x-ray comes from below the
patient and gets scattered from the patient and coming towards
the operator so actually it's the legs get the higher dose during
any sort of x-ray guided procedure. Sometimes we're forgetting
importance of shielding the legs 'cause we think the legs,
whatever the muscles, the bones, they're fine. But as the study
shows, it's not just the muscles and the bones there but the
whole circulation blood gets exposed to x-ray in the lower
extremity circulation and that can translate to many other
potentially adverse events.


Dr Carolyn
Lam:               
Manos, I love that you manage both these papers. What important
messages for increase in risk awareness. This was really very,
very well accomplished by both these papers. As well by the
editorial that you asked for and that was so well written by Dr.
Charles Chambers on both these papers. But beyond risk awareness,
what I really love is what you brought up just a while earlier
about risk reduction and methods that we can take, for example,
in the second paper, by Dr. Modoari and colleagues about
shielding the legs. What are the implications for example,
wearing a helmet or shielding the head for interventional
cardiologists? What do you think?


Dr Manos
Brilakis:           
These are very, very good points. The reality is for the head
there have been a couple studied that looked at shielding with
lead caps or there's some lead free caps that can be worn and
also there are radiation protective glasses. However, what was
interesting, there was a paper earlier last year that showed that
because the radiation actually comes from below the operator that
wearing those helmets, although it seems appealing, it is simple
to do obviously, it actually did not significantly reduce the
dose to the brain and it only partially reduced the dose to the
eyes. Though shielding is useful but may not be as good as we
think it is.


                                               
In my mind, the starting point of all this is the basics of
radiation safety which again, sound very simple and we learn
about them in the beginning of training, unfortunately what
happen is people tend to forget them as time goes by. These are
things like don't step on the x-ray pedal unless you need to look
at the pictures and that's very common done. People just have
this heavy foot syndrome. They keep on x-raying when they don't
need to. There's also the important things having the patient as
high as possible and the detector as close to the patient so
there is not as much distance for the x-ray to travel. Things
like using low, not very steep angles so there is not as much
radiation because they have to go through less amount of tissue.
And there's some technologies actually coming along there's some
technologies that focus the radiation beam only specific areas.
And cut the overall dose. And there are x-ray machines that also
can have much less radiation overall for the patient and the
operator. As you said, having good shielding habits is very
important.


Dr Carolyn
Lam:               
Yeah, that's exactly it. That risk awareness should lead to
action. I'm just curious, who do you think should primarily take
hold of these risk reduction and safety procedures and the
enforcement and so on? Us as a community, but what do you think
of the role of things like professional societies, quality
improvement programs, FDA even?


Dr Manos
Brilakis:           
It's a great point. What we hear here Maria's comments on this as
well. But my feeling is absolutely societies are very important
for leading these efforts and they do have actually guidelines.
There's procedural guidelines for radiation protection. But the
end of the day it's the individuals themselves, the operators,
each and every one who is in charge of this in their care or his
own cath lab and their procedures.


Dr Maria Andreassi:        I
agree. We all of our findings can contribute to the increase of
cross cultural assessment in cath lab and by promoting the
diffusion but not the reduction technologies whereas diligent
about your protection habits. Moreover it is important to let the
design, the relationship between occupational radiation exposure,
clinical risk and there are very important future studies
studying larger population. We should focus on the molecular
epidemiology studies by using biomarkers and this will be
clinical and points as early predictors of a clinical event.
Because this information is a model likely to better define the
risk of radiation use disease at low doses as a comparative tool,
the classical epidemiological approach that require a very large
sample sizes spread over [inaudible 00:20:51].


                                               
Now it's time where largest studies involving scientific
societies at an international level. Possible breaking the
additional exposure in already recruited the Roth case. And by
combining the conventional epidemiology, and the molecular
studies and the expected results to better define the clinical
risk as a good lesson to implement a more effective protection
program. And better as the surveillance at the individual level.


Dr Carolyn
Lam:               
That is wonderful. And thank you, this truly is an international
call, isn't it? Another thing that we should keep in mind that
all measures that we use to protect our patient from receiving
excessive radiation is likely to help us as well as
cardiologists.


                                               
Thank you so much, both of you, for joining me today on this
podcast. What an important message and I'm sure that our
listeners will agree. Thank you listeners for joining us. Tune in
again next week.