Circulation October 3, 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 striking results from the ASSERT 2 trial
of the prevalence of subclinical atrial fibrillation detected
with implantable monitors in a group of high-risk older
individuals. Much more soon, right after these summaries.


                                               
The first original paper in this weeks' journal shows for the
first time that myocardial edema, in the week after STEMI in
humans, is a bimodal phenomenon. First off, there is Dr.
Fernandez Jimenez and Barreiro-Perez, corresponding author Dr.
Ibañez, and colleagues from CNIC in Madrid, Spain, evaluate that
the time course of edema reaction in 16 patients with anterior
STEMIs successfully treated by primary angioplasty compared to 16
matched controls using cardiac magnetic resonance and assessing
its implications for myocardium at risk quantification. The STEMI
patients were scanned serially within the first three hours after
reperfusion and at, one, four, seven and 40 days, while controls
were scanned once. Furthermore, they performed an experimental
study of 20 pigs undergoing 40 minute ischemia reperfusion,
followed by serial cardiac magnetic residence exams at 120
minutes, one, four and seven days after reperfusion.


                                               
The authors found that am initial wave of edema appeared abruptly
at reperfusion, but it was significantly attenuated by 24 hours.
The initial wave of edema was followed by a second or differed
healing related wave of edema several days after reperfusion,
reaching a plateau around four to seven days after myocardial
infarction. Of note, cardiac magnetic resonance myocardium at
risk quantification at 24 hours post-reperfusion severely
underestimated the infarct size.


                                               
In summary, post-MI edema in patients follows a bimodal pattern,
which affects cardiac magnetic resonance in estimates of
myocardium at risk. The dynamic changes in post-STEMI edema,
highlight the need for standardization of cardiac magnetic
resonance timing to retrospectively delineate myocardium at risk
and quantify myocardial salvage. According to the present
clinical and experimental data, a time window between day four
and seven, post-MI, seems a good compromise for standardization.
However, further studies are needed to study the effect of other
factors on these variables.


                                               
The next paper sheds light on molecular mechanisms underline the
progression of atherosclerosis, involving multiple inflammatory
events, as well as the counteraction by inflammatory responses in
cells such as the endothelium, circulating monocytes and resident
macrophages in the arterial wall.


                                               
Co-first authors, Dr. Li and Martin, corresponding author Dr.
Shyy from Xi’an Jiaotong University Health Science Center and
University Health Science Center and University of California,
San Diego and colleagues, analyzed RNA seek data to identify
cholesterol oxidation and e-flux genes regulated by Kruppel-like
factor 4, which is a key anti-inflammatory transcription factor.
They found that Kruppel-like factor 4 upregulates cholesterol 25
hydroxylase and liver X receptor in vascular endothelial cells
and macrophages. In further in vitro and in vivo experiments,
they show that access enhanced reverse cholesterol transport from
the vascular wall, mitigated inflammation through suppression of
sterile regulatory binding protein two and NOD-like receptor
family hiring pyrin domain containing protein three inflammasome
in endothelial cells and also promoted cholesterol e-flux in M1
to M2 transition in macrophages.


                                               
In summary, Kruppel-like factor 4 trans-activates cholesterol 25
hydroxylase and liver X receptor, promoting the synergistic
effects between individual cells and macrophages to protect
against atherosclerosis susceptibility, and this may therefore be
a therapeutic target for cardiovascular disease.


                                               
The next study provides data on the safety and efficacy of a
novel cobalt alloy-based coronary stent eluting the
antiproliferative agent, ridaforolimus, for treatment of patients
with coronary artery disease.


                                               
Dr. Kandzari from Piedmont Heart Institute in Atlanta, Georgia
and colleagues, reported the primary results of the bionics
trial, which was a prospective international, one-to-one
randomized trial conducted to evaluate in a noninferiority
design, the relative safety and efficacy of ridaforolimus-eluting
stents compared to slow release zotarolimus-eluting stents among
1,919 patients at 76 centers undergoing PCI. At 12 months, the
primary endpoint of target lesion failure was 5.4% for both
devices, thus meeting the prespecified criteria of noninferiority
of ridaforolimus stent compared to the zotarolimus stent.


                                               
Angiographic and intravascular ultrasound measures of restenosis,
late lumen loss and nepintimal hyperplasia measured at 13 months,
were similar in both devices. Treatment with the
ridaforolimus-eluting stent resulted in low rates of myocardial
infarction, repeat revascularization and stent thrombosis, and
results were consistent in predefined patients and lesion groups.
The authors therefore concluded that these results support the
safety and efficacy of ridaforolimus-eluting stents in patients
representative of every day clinical practice.


                                               
Well, that wraps it up for your summaries. Now, for our future
discussion.


                                               
Today for our future discussion, we are going to talk about a
true global public health problem. It's a condition that affects
33 million people worldwide, a number that is expected to double
by 2050, and what we're talking about is atrial fibrillation.
Those are the numbers of just what we know of detected atrial
fibrillation, but today's paper deals with silent subclinical
atrial fibrillation and the results of the ASSERT 2 trial. I'm so
pleased I have the first and corresponding author with us today,
Dr. Jeff Healey from Population Health Research Institute at
McMaster University in Hamilton, Ontario. Welcome, Jeff.


Dr. Jeff
Healey:                
Good morning.


Dr. Carolyn
Lam:              
Also on the show today is Dr. Sami Viskin, associate editor from
Tel Aviv Medical Center. Hi, Sami.


Dr. Sami
Viskin:                
Hi. Hello, everybody.


Dr. Carolyn
Lam:              
Jeff, from ASSERT to ASSERT 2, could you give us a bit of the
picture of what made you do ASSERT 2 and what have we learned?


Dr. Jeff
Healey:                
The ASSERT trial was a large 2,500 patient trial in patients in
with pacemakers and also implantable defibrillators and it was
really an easy first place to study this entity of sub-clinical
atrial fibrillation because, of course all of these patient had
implanted devices with electrodes in their atrial where they
could report all of the internal activity continuously for many
years at a time. This was done with really no incremental costs
or inconvenience to the patient, the data were already being
collected, so in ASSERT we asked the question, how common is
atrial fibrillation as it is not detected clinically and is it
associated with stroke? What we found was that over time,
somewhere between 30% and 40% of patients with an implemented
device developed atrial fibrillation, which we termed subclinical
atrial fibrillation, because this was not detected by the usual
clinical mean. Great results, very interesting, but begged the
question, is this a unique entity that we see only in pacemaker
patients or if you just took older individuals in the more
general population, would you see subclinical atrial fibrillation
as well? That was really the impetus for doing that ASSERT 2
trial in patients who are over the age of 65, had cardiovascular
condition, placed them at increased risk or stroke in atrial
fibrillation, but did not have implanted devices.


Dr. Carolyn
Lam:              
Indeed, Jeff. That's a beautiful set up. The ASSERT was really
quite a landmark study suggesting that what we know as clinical
may be just the tip of the iceberg, isn't it? Now you've extended
it, and I think it'd be really important for the audience to
understand that ASSERT 2 was really a high risk cohort. Could you
maybe tell us a little bit more of what you did and what more we
learned?


Dr. Jeff
Healey:                
Sure. These were typical patients who might be attending a
cardiology clinic, an outpatient general medicine clinic who did
not have pacemakers and did not have any history of atrial
arrhythmias, but you're right, they were high-risk. These were
patients over 65 who have had clinical risk factors, things like
hypertension, or diabetes, but also some other marker of
increased risk such as a BNP that was elevated or left atrial
enlargement.


Dr. Carolyn
Lam:              
Yeah and your findings were so striking. Tell us.


Dr. Jeff
Healey:                
What was quite was surprising was, indeed, we found that in the
non-pacemaker, non-defibrillator population from ASSERT 2, we
also found high prevalence of subclinical atrial fibrillation.
This was really quite surprising. In fact, it was many times
higher than we had predicted. We found that over time, the annual
risk of developing atrial fibrillation in this cohort was 34.4%
per year, which is truly astounding number of patients who
developed atrial fibrillation.


Dr. Carolyn
Lam:              
That's like one in three of such patients experiencing at least
one of these episodes lasting at least five minutes? That's
really impressive.


Dr. Jeff
Healey:                
It was high.  You could look into that study and find groups
where the risk was even higher, so we chose to cut off left
atrial volume of 58 millimeters and not correspondent with the
median volume of the population series of Olmstead County for
people over the age of 65 who came in for an echocardiogram, and
that was the minimum left atrial size to get into the trial. If
you then looked at within the ASSERT 2 trial and looked at the
volumes within the trial, somewhere around 72 1/2 milliliters, if
you looked at the patients who had the top of atrial size, that
risk was as high 50% per year, so one in two.


Dr. Carolyn
Lam:              
Another thing I noticed though about your results is that the
frequency of these episodes, it's not that frequent, and so what
we would do typically in a 24-hour monitoring or even a seven-day
monitoring would have captured only a small proportion of these.
Isn't that the case, Jeff? Could you give us some numbers there?


Dr. Jeff
Healey:                
Yes, of course. The episodes that qualified were at last five
minutes in duration, we then do longer episodes in course, but
these were much less frequent in the single digit percent risk,
and what we found was there were, as you say, quite infrequent.
So with the standard 24-hour halter monitor, for example, you
would have had a very low pickup. It really goes to show that the
longer you monitor, the more you will find. I think that's the
key message out of this study and other studies like it.


                                               
I think conversely, you also have to realize that the more you
look, or the harder you look, you may be uncovering atrial
fibrillation that behaves differently than atrial fibrillation
you find, for example, in the single 12 lead ECG. We have found,
and others have found, that the risk of stroke we find when we
would have short episode picked up only with long term continuous
monitoring is real but it's much lower than we see with atrial
fibrillation that was picked up by ECB where patients are
presenting in emergency rooms stroke with symptoms.


Dr. Carolyn
Lam:              
That's such relevant points, and it really brings up the
unanswered questions perhaps, exactly what is the correlation
with stroke risk? What should we do about it? Sami, I'm sure you
have other questions when you handle this paper and we had so
many discussions among the editor, would you like to just start
the ball rolling in some of these considerations?


Dr. Sami
Viskin:                
Well, actually, we understood from the beginning of the study was
not powered to show any difference in outcome by intervention, by
treating any of these patients that had discovered atrial
fibrillation with anticoagulation, so we took this paper as what
it is, a paper that shows the unexpectedly high privileges of
atrial fibrillation in patients who have neither symptoms nor
electrocardiographic documentation of atrial fibrillation when
they undergo implantation of our recording device. So we took
this paper for what it is, a very interesting finding that opens
the door for new studies, testing perhaps the value of
intervention with anticoagulation at an earlier stage.


Dr. Carolyn
Lam:              
Yeah, I agree. I'd love to hear Jeff’s thoughts on what those
next steps may be, but just to point out to the audience, I mean,
at the moment, our decisions on whether to anti-coagulate, like
the CHADSVASC score and so on, doesn’t really take into account
the type of atrial fibrillation or the duration of atrial
fibrillation? Does it? What do we do now? What do we do in the
context of the fact that results, like the COMPASS trial, that
maybe just based on the presence of vascular disease, we should
anti-coagulate, right? Jeff, how about your thoughts? What are
the next steps?


Dr. Jeff
Healey:                
You're right. I mean, is there a value for empirically
anticoagulating individuals. That's really going to boil down to
the individuals with an absolute risk of stroke and how well they
do on anticoagulants. Good question.


                                               
In the post-stroke world or post-cryptogenic stroke, which we now
report to as [inaudible 00:16:48], these individuals are being
evaluated with two large clinical trials, looking at this idea of
just empiric anticoagulation with low dose, NOAC in comparison to
aspirin.  These trials are ongoing, and they expect to
report findings by the end of 2018.


                                               
In the general population, no such large scale trial is ongoing
at the present time. You mentioned COMPASS and the big COMPASS
results were clearly a big result at the European Society
meeting, but it must be clarified that the dose of NOAC or
rivaroxaban used in COMPASS was not the typical dose that we
would use in the treatment of patients with atrial fibrillation,
so much lower. I think we have to be careful when we're talking
about doses that may be different 5 to 10 fold and what is then
coagulating a patient and what is not. I think, certainly, I
would not consider the COMPASS tests right now to be an effective
atrial fibrillation dose, but as we've discussed, subclinical
atrial fibrillation is different and we may have further data in
the future.


                                               
Now, how do we get there? I think many people are aware of two
ongoing trials, the ARTESIA trial, which is run by our group, the
NOAH-AF Trial run by Kirchof and the group from Birmingham and
the AF-NET organization, and these two ongoing trials have taken
this question back again, so the pacemaker population that we are
enrolling thousands of patients with pacemakers and
defibrillators who have these short episodes, and they're being
randomized treatment with a full dose new oral anticoagulant vs
aspirin. These trials are ongoing, and I think these trials and
the pacemaker population will actually give us the answer to what
is the risk benefit for treating, so interesting course of event.
We started in the pacemaker population to show there was risk for
these short episodes, that this was hotly debated 10 - 15 years
ago, and now we take ASSERT 2 and other trials into the
non-pacemaker population to show that this is actually a problem
for older individuals in general, and now the third step, go back
into the pacemaker clinic again and to do trials to study the
effectiveness in therapy.


Dr. Carolyn
Lam:              
Great point and great takeaways. How about, Sami? What do you
think would be the take-home message for clinicians at this
moment based on what we know now and based on this new data?


Dr. Sami
Viskin:                
Well, the message is clear, the message is that atrial
fibrillation is far more prevalent than what we think it is, the
message is that for every event of atrial fibrillation that we
feel we probably have many events that we don't feel we should be
distrustful about judging the decision to anti-coagulate or not
based on symptoms, and I'm referring now to patients who already
have one event documented of atrial fibrillation and are waiting
until they feel the next one, before they start taking
anti-coagulations. This is another warning about how we should be
careful about trusting symptoms when deciding to treat and when
not to treat. I just said this opens a new door for a new line of
studies, looking at how early to intervene with anticoagulation,
what dosage should be used for these patients who probably have
lower burden of atrial fibrillation. If you can see that the
patients who have atrial fibrillation documented on the electric
cardiogram, as patients who simply have a higher burden and
therefore they are more likely to come up with documentation on a
regular ACG, so perhaps those only have subclinical atrial
fibrillation have a lower burden, perhaps they can benefit from
lower doses of anticoagulation, but these are all fit, that need
to be proven by trials.


Dr. Jeff
Healey:                
It is not only an issue for implanted devices but with the
implantable cardiac monitors, this is now relevant for many other
patients who have these devices implanted for things like
syncope, but also there's been a lot of progress in the last 5 to
10 years on surface-attached based monitors or other types of
monitors that can be with patients for days, weeks and even
months, and we're all grappling with this in clinical medicine,
what to do with a person with 25 beats of an atrial tachycardia
or 37 seconds on a 30-day monitor? It's all an issue of the
density, the burden of arrhythmia, and we do believe there is
some gradience in the risk of stroke ... You're right, the
treatment is not obvious, but we should take our treatment for
patients who are in atrial fibrillation a lot or all the time,
and simply apply it upstream like, that we may have very
different treatment or approaches that are more tailored to
individual patient risk.


Dr. Carolyn
Lam:              
Thanks, Jeff, and thank you so much, Sami. Congratulations, Jeff.
We discussed a lot of other questions that need to be answered,
but you've really opened the door to look at some of these
questions with your paper today and we're really very proud to be
publishing your paper in this week's journal.


                                               
Thank you very much, listeners for joining us this week. Don't
forget to tune in again next week.