Circulation August 29, 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. Our feature paper this
week tells us more about aortic wall inflammation, and how this
predicts abdominal aortic aneurysm expansion, as well as need for
surgical repair. Much more, right after these summaries.


                                               
Our first original paper sheds light on a novel mechanism for
adult cardiac regeneration. This is a paper from first authors
Drs. Wang, and Lee, and corresponding authors Dr. Chen, Houser,
and Dr. Jeng from Third Military Medical University from
Chongqing, China.


                                               
In an elegant series of experiments using mouse models, the
authors showed that mature adult cardiomyocytes could re-enter
the cell cycle and form new cardiomyocytes though a three-step
process: of dedifferentiation, proliferation, and
redifferentiation. Intercellular calcium signals from neighboring
functioning cardiomyocytes through gap junction induce the
redifferentiation process. Furthermore, they showed that this
mechanism contributed to new cardiomyocyte formation in post MI
hearts in mammals. In summary, this study contributes to our
understanding of adult cardiac regeneration and could lead to
novel strategies to repair the injured heart.


                                               
The next paper provides mechanistic data that may explain why
thrombotic complications are more prevalent in patients with
diabetes, and why some anti-platelet drugs may have limited
efficacy in patients with diabetes. In this paper by first
author, Dr. Hu, corresponding author Dr. Ding, and colleagues
from Fudan University in Shanghai, China, the authors show that
platelets of patients with Type 2 diabetes express high levels of
activated P2Y12 receptor.


                                               
The P2Y12 inverse agonist inhibited P2Y12 activity of platelets
from diabetic patients and rats, more than Cangrelore, leading to
a stronger in-vivo antithrombotic effect in thrombosis rat models
with diabetes. Increased platelets P2Y12 receptor expression in
diabetes was mediated by a high-glucose reactive oxygen species,
NF-kappaB pathway. In summary, platelet P2Y12 receptor expression
was shown to be significantly increased, and the receptor was
constitutively activated in Type 2 diabetic patients, which
contributed to platelet hyperactivity, and limited anti-platelet
drug efficacy in Type 2 diabetes. 


                                               
The next paper tells us that the majority of cardiovascular
disease events are now occurring amongst adults with a systolic
and diastolic blood pressure of less than 140 over 90 millimeters
mercury. Prior data have shown us that the majority of incident
cardiovascular disease events occurred among U.S. adults with
higher systolic and diastolic blood pressures of above 140 over
90. However, over the past several decades, blood pressure has
declined and hypertension control has improved. Thus, in the
current study, Dr. Tajeu and colleagues from Temple University
College of Public Health in Philadelphia estimated the percentage
of incident cardiovascular disease events that occur at blood
pressures below 140-90 in a pooled analysis of three contemporary
U.S. cohorts: the Reasons for Geographic and Racial Differences
in Stroke, or, REGARDS study, the Multi-Ethnic Study of
Atherosclerosis, or MESA study, and the Jackson Heart study.


                                               
In these three U.S. cohorts that enrolled after 2000, more than
60% of incident cardiovascular disease events occurred among
participants with blood pressures below 140 over 90 millimeters
mercury. In the 2001 to 2008 National Health and Nutritional
Examination survey mortality follow-up study, 58% of
cardiovascular disease stats occurred in U.S. adults with blood
pressures below 140 over 90. Among participants taking
anti-hypertensive medication, with blood pressures below 140 over
90, only one-third of those who are eligible for starting
treatment were taking one, and approximately 20% met the SPRINT
eligibility criteria.


                                               
In conclusion, while higher blood pressure levels are associated
with increased cardiovascular disease risk, in the modern era the
majority of incident cardiovascular disease events occur in U.S.
adults with blood pressure below 140 over 90. Although absolute
risk and cost effectiveness should still be considered,
additional cardiovascular disease risk reduction measures for
adults with blood pressure less than 140 over 90, and at high
risk for cardiovascular disease, may be warranted.


                                               
Well, that brings us to the end of our summaries. Now, for our
feature discussion.


Dr. Carolyn
Lam:              
On today's podcast discussion, we will be talking about aortic
wall inflammation as a possible functional, or biological,
imaging bio-marker that may add to the usual structural
measurements of size that we use to predict abdominal aortic
aneurysm expansion and rupture. Now, to discuss this very
important paper, we have the corresponding author, representing
the MA3RS study investigators, Professor David Newby from the
Center for Cardiovascular Science in Edinburgh, as well as a
familiar voice now, Dr. Joshua Beckman, associate editor from
Vanderbilt University. Welcome, gentlemen.


Professor David Newby: Hi, there.


Dr. Joshua Beckman:      So great to be
here again, thanks for having me.


Dr. Carolyn
Lam:              
So great that you're back again, Josh! But David, let's start
with you. Could you just summarize what this trial was about and
your main findings?


Professor David Newby: Sure, so this was a major clinical trial
that we undertook in the U.K. and Scotland. We approached
patients who were in a surveillance program who had an abdominal
aortic aneurysm, and we asked the question, "Is there anything we
can do better than just serial ultrasound measurements that
currently are stunned to this care?" So, in Edinburgh, we
developed a technique using ultrasmall, superparamagnetic
particles of iron oxide, which is a bit of a powerful ... so we
shortened that to USPIOs; these are really small iron particles
that are so small they can cross vascular spaces and they get
gobbled up by tissue resident macrophages, and then causes a
signal that we can detect on magnetic residents' scanning MRI.


                                               
So we were really asking the question, "Can we do better than
ultrasound by using what we call USPIO-enhanced MRI?"


Dr. Carolyn
Lam:              
So a biological or functional imaging parameter versus just
structural. And so, what were your main findings?


Professor David Newby: We recruited around 361 patients and
ultimately 341 went into the trial because of various exclusions,
et cetera. And we followed these patients up for, on average,
around three years. And so we were following it up every six
months with ultrasound, with other various assessments, and
ultimately what we found was that the USPIO-enhanced magnetic
residents' scan was positive in around half of patients, and in
those patients that took up the USPIOs in their abdominal aortic
aneurysm wall, those patients, their aneurysms expanded quicker.
So rate of expansion was higher, and they went on the have the
primary event of either elective repair, or rupture. And, don't
forget, that the clinicians who were looking after these
patients, they didn't know the results of the MRI so it didn't
influence their clinical minds, when this was completely
independent of the clinical team.


                                               
So, for the first time, we demonstrated that imaging or tracking
macrophages in the abdominal aortic wall could, indeed, predict
both disease progression and clinical outcome.


Dr. Carolyn
Lam:              
And Josh, you know, no one can say it better than you: could you
just describe what we discussed as the editors about the
significance of such a finding?


Dr. Joshua Beckman:      I think there's
a few things to take home from these three that are really
incredible. First, David, were you surprised at the concordance
between the USPIO-enhanced imaging and smoking, or was that
something that you expected?


Professor David Newby: That was a big surprise. That was,
actually, as we discussed in the manuscript, quite an interesting
finding, and as always with an interesting find, we dig around in
the background, and it actually gets more and more exciting and
plausible because of the mechanistic work that we'd seen in the
pre-clinical science that preceded our trial. So yes, it was a
surprise, but actually the more we got into it, the more it made
sense.


Dr. Joshua Beckman:      One of the
other things that I think is really important to talk about is
how you get this study done, and one of the things I found
incredibly impressive ... I am unaware of any other multi-sensor
MRI study like this. How did you organize this amongst the
different institutions?


Professor David Newby: It can be a bit of a challenge. So I've
done quite a few multi-sensor trials in Scotland, and imaging
trials, and the community in Scotland actually is very, very
supportive and we got a good network of folks. So the three
centers are actually two imaging centers: one in Edinburgh one in
Glasgow, a further recruitment center in a city just in the
center of Scotland, Sterling. And the patients ... we were able
to obviously make sure the scanners did the same protocols;
fortunately, they were the same scanner, make and model. So that
all obviously helped, but we had a lot of inundation, phantom
work, to make sure both centers got things right.


                                               
But there was a huge motivation to get this done, and I'm
indebted to Charles Riditi and Colin Barrie in Glasgow for doing
the, and supporting the, imaging work, and also a medical
physicist here in Edinburgh, Scott Semple, who'd done a lot of
the work to get this to happen. So there's a teamwork in Scotland
and the NHS, where the access to patients are in the screening
program as well, which made recruitment really well and very
efficient. And we started exactly to target, which is pretty
unusual in clinical trials, often takes longer to recruit
patients, but it was a great team effort. The imaging quality, we
checked, verified, centrally read, and it was really good to see
it delivered in that way.


Dr. Joshua Beckman:      Do you think
that agent, the iron oxide particles, is going to be the contrast
agent, I guess, of the future, or do you think because it is now
so consistent with smoking, it's gonna be more of an
investigational tool?


Professor David Newby: So there's a couple of things to say here
on ferumoxital, which is the USPIO we used. It's currently
licensed in the U.S. for the treatment of anemia and chronic
renal failure, but it can also be used as an imaging agent and
actually this, I think increasingly, might have a role; not just
in aneurysms, but elsewhere. So the first thing you can do is
actually do angiography with this agent. [Obviously gadolinium is
getting a lot of press at the moment, with problems with warnings
coming out, of residual brain deposition, and so on. With the
USPIOs, you can use this in renal failure patients, so again,
another contraindication for us to concern about: NSF in renal
failure patients. So actually, for angiography, I think it's
going to have an increasing role.


                                               
For imaging of inflammation, we've previously demonstrated that
you can track inflammation post-myocardial infarction, so you can
see air is lighting up following myocardial infarction. We have
some papers out on that, and I think, if you are in the business
of looking at cellular inflammation, macrophage trafficking, then
this technique really can be helpful.


                                               
When we come to aneurysm studies, I think it is less clear
because ultimately, doing a quick ultrasound, in fact can give
you the information together with all of the clinical risk
factors, like smoking, and you get to the same end point without
doing the MRI. Then, clearly, it's not going to be that
impactful. Having said that, I think sometimes we will have
patients who've got all this information and we're not sure which
way to go. So I think it could be used as an almost umpire test,
if you're not sure whether to proceed with surgery or not. And I
think, also, if we discover new agents that are anti-inflammatory
that may impact on disease progression, with a normal therapy,
then clearly this might be a good buyer market to use in future
therapeutic trials.


Dr. Joshua Beckman:      Yeah, I
actually see a huge potential for the testing of new agents, to
see whether or not it reduces the inflammation that's associated.
I'm gonna ask you a theoretical question, if that's okay with
you. Part of the inflammatory process in the aneurysm is based on
oxidative stress, but I've always wondered if you provide more
oxygen, which may enhance the oxidative stress reaction, are you
actually worsening the reaction at the time you're doing the
study? Is that possible, or am I just concerned about nothing and
making it up?


Professor David Newby: Well, obviously your [inaudible 00:13:19]
stressors is important in all of cardiovascular disease, and if
you increase oxygen supply, maybe you indeed induce more
oxidative stress. In the context of an aneurysm, often there's
quite an hypoxic state in the aneurysm wall, because obviously
the intraluminal thrombus can buffer the wall itself from it,
obviously the vasovasorum come in, but they may not be as
efficient in doing that. Some of the areas that we're seeing
light up probably are quite hypoxic, so they'll be in an
oxygen-deprived state. So I think that needs to be put in the
balance, too, and there has been some suggestion that iron
particles can increase oxidative stress, and it has been
suggested maybe harmful; we've not seen that, we've had
absolutely no adverse reactions at all in all of our patients. We
had one patient whose blood pressure fell a little bit, but we
didn't have to medically intervene at all, so it was just
observed and it passed; of course it might be due to many things.


                                               
We've also studied this in patients with myocardial infarctions,
I've said, also bypass surgery, people who've had bypass surgery.
We've also published on using these agents there, and again,
we've seen absolutely no adverse reactions. And you would've
thought, in the context of those situations, if you were going to
see an adverse effect you would've seen it behind.


Dr. Carolyn
Lam:              
David, I've got a question for you. I think you mentioned, a
little bit earlier, that end of the day this enhanced MRI did not
improve the risk stratification beyond the current predictors of
clinical outcome in abdominal aortic aneurysms, but what are the
next steps for you?


Professor David Newby: There's a couple of things, which we've
been thinking through. Firstly, I think the primary end point of
the trial was mostly driven by repair, and when we looked at the
emergent events, so dying, and rupturing, the signal got stronger
and very close to statistical significance. And obviously when
you've got a population of patients whose elective surgeries
mostly dominated by the ultrasound scan decision, therefore makes
it difficult to prove, on top of that, the MRI will have value.
So it's quite high, and on a difficult bar to cross, so some of
the thoughts we've had are thinking about predicting rupture,
rather than repair. And there will also be potential for actually
doing a trial, where we actually base decisions on the aneurysm,
and if you've got an intermediate category of patient, where
you're not sure which way to go, those patients you then do use
as an arbiter, and that might have, therefore, proof or value for
it.


                                               
And the final area that we're probably thinking about exploring
is, "Okay, paths for macrophages." Is there other
pathophysiological processes that we might want to explore with
other agents, that might predict aneurysm growth and rupture even
stronger, and macrophage inflammation? So those are some of the
thoughts that we've had about where the next steps will be.


Dr. Joshua Beckman:      This is an
incredible amount of work and I always think it's important to
make clear to everybody who's listening to this podcast that,
even though we may not all do the same kinds of research, it
needs to be made clear that having a multi-sensor study in this
topic, with this technique, is incredibly impressive. And the
physiology that was brought forth, in addition to the clinical
stuff that we just heard about, I think is what makes this worthy
of a podcast.


                                               
Dr. Newby, thanks so much for participating.


Professor David Newby: Thank you so much, that's very kind. And
just to reiterate, it has been a long journey and a huge effort,
but we're reaping the rewards now, and it's nice to see the data
being published in circulation.


Dr. Carolyn
Lam:              
Gentlemen, it has been so wonderful having you here to discuss
this. Thank you so much for your time.