Circulation October 18, 2016 Issue

Carolyn:
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 Centre and
Duke National University of Singapore. Have you ever wondered
what the clinical implications of very brief episodes of
device-detected atrial tachyarrhythmias are? Well, we will be
discussing this with novel data from the RATE registry in just a
moment. First, here's your summary of this week's journal.


 
 
The first study provides the first evaluation of the Sweden
nationwide abdominal aortic aneurysm screening program. Of almost
303,000 men invited for screening, 84% attended. The prevalence
of screening detected abdominal aortic aneurysm was 1.5%. After a
mean of 4.5 years, 29% of patients with aneurysms had been
operated upon with a 30-day mortality rate of 0.9%. The
introduction of screening was associated with a significant
reduction in aneurysm-specific mortality. The number needed to
screen to prevent 1 premature death was 667, while the number
needed to operate on to prevent 1 premature death was 1.5.


 
 
Furthermore, the authors showed that their screening program was
highly cost-effective in the contemporary setting in Sweden.
These findings confirm results from earlier randomized controlled
trials in a large population-based setting, and may be important
for future healthcare decision-making. This and the diverse
requirements for efficient population screening for abdominal
aortic aneurysm, from program management to maintaining skills in
open repair are discussed in an excellent accompanying editorial
by Dr. Cole from Imperial College London.


 
 
The next study looks at thoracic epidural anesthesia and suggests
that caution may be needed in patients with or at risk for right
ventricular dysfunction. You see, thoracic epidural anesthesia
involves blockade of cardiac sympathetic fibers, which may affect
right ventricular function and interfere with the coupling
between the right ventricle and right ventricular afterload. Dr.
Wink and colleagues from the Leiden University Medical Center
therefore used combined pressure volume conductance catheters to
study the effects of thoracic epidural anesthesia on right
ventricular function and ventricular pulmonary artery coupling in
10 patients scheduled for lung resection.


 
 
Thoracic epidural anesthesia resulted in a significant reduction
in right ventricular contractility, stroke work, dP/dt max and
ejection fraction. This was accompanied by a reduction in
effective arterial elastance such that ventricular pulmonary
coupling remain unchanged. Clamping of the pulmonary artery
increased right ventricular contractility but decreased
ventricular pulmonary coupling. These effects of increased
afterload were the same before and after thoracic epidural
anesthesia. In conclusion, therefore, thoracic epidural
anesthesia impaired right ventricular contractility but did not
inhibit the native positive ionotropic response of the right
ventricle to increase afterload. These findings are clinically
relevant for daily practice in cardiothoracic surgery because
pulmonary hypertension is frequently encountered, and right
ventricular function is an important determinant of early and
late outcomes.


 
 
The next study suggests that the use of point of care hemostatic
testing may have a place in the management of patients undergoing
cardiac surgery. Dr. Karkouti and colleagues of the Toronto
General Hospital hypothesized that point of care hemostatic
testing within the context of an integrated transfusion algorithm
would improve the management of coagulopathy in cardiac surgery,
thereby reducing blood transfusion. They therefore conducted a
pragmatic multi-center stepped-wedge cluster randomized
controlled trial of a point of care based transfusion algorithm
in 7,402 consecutive patients undergoing cardiac surgery with
cardiopulmonary bypass in 12 hospitals in Ontario, Canada. They
found that the trial intervention reduced rate of red cell
transfusion with an adjusted relative risk of 0.91 and a number
needed to treat of 24.7.


 
 
The intervention also reduced rates of platelet transfusion and
major bleeding but had no effect on other blood product
transfusions or major complications. These findings that point of
care testing improved management of coagulopathy in cardiac
surgery support the consideration of their broader adoption in
clinical practice.


 
 
The next study provides experimental evidence that brings us one
step closer to therapeutic targeting of arterial leukocyte
recruitment in the context of atherosclerosis. In this study from
first author Dr. Ortega-Gómez, corresponding author Dr. Soehnlein
and colleagues from LMU Munich, authors focus on cathepsin G,
which is stored in neutrophil and azurophil granules and
discharged upon neutrophil activation. They studied site-specific
myeloid cell behavior after high-fat diet feeding or TNF
stimulation in the carotid artery, the jugular vein, and
cremasteric arterioles and venules in APOE E and Cathepsin
G-deficient mice.


 
 
Their studies revealed a crucial role for Cathepsin G in arterial
leukocyte adhesion, an effect that was specific for the arteries
and not found during venular adhesion. Consequently, Cathepsin G
deficiency attenuated atherosclerosis but not acute lung
inflammation. Mechanistically, Cathepsin G was immobilized on
arterial endothelium, where it activated leukocytes to firmly
adhere, engaging endocrine clustering, a process of crucial
importance to achieve effective adherence under high-sheer flow.


 
 
Therapeutic neutralization of Cathepsin G specifically abrogated
arterial leukocyte adhesion without affecting myeloid cell
adhesion in the microcirculation. Repetitive application of
Cathepsin G-neutralizing antibodies really allowed the inhibition
of atherogenesis in the mice. Taken together, these findings
presented evidence of an arterial-specific recruitment pattern
centered on Cathepsin G adhesion, thus representing a potential
novel strategy and target for the treatment of arterial
inflammation. Well, that wraps it up for the summary of this
week's journal. Now, for our featured discussion.


 
 
Our feature paper for today discusses the clinical implications
of brief device-detected atrial tachycardias and really novel
findings from the RATE registry. I'm so happy to be here with the
first and corresponding author, Dr. Steven Swiryn from Feinberg
School of Medicine, Northwestern University. Hi, Steven.


 
Steven:
Good morning.


 
Carolyn:
We also have with us Dr. Mark Link, associate editor from UT
Southwestern. We all know that prolonged episodes of atrial
tachycardia or atrial fibrillation are associated with increased
risk and that if we anticoagulate those with a high CHA2DS2–VASc
score, we can lower the risk of stroke. Now, the European Society
of Cardiology guidelines also say that recent data reinforced the
assumption that even brief episodes of silent atrial fibrillation
may convey an increased risk of stroke. We also know that prior
studies have looked at device-detected atrial fibrillation.
Steven, I'd really love if you could start by telling us what
makes your study different. What was the main thing you were
trying to look at?


 
Steven:
Well, one reason it's attractive to use the device population,
patients with pacemakers or defibrillators, to look at these
issues is because devices have a very high likelihood of
detecting episodes of atrial fibrillation whereas symptoms or
single 12 EKGs miss a lot of atrial fibrillation, so the
sensitivity is much higher, although not perfect. The problem is
that very brief episodes of atrial fibrillation are very poorly
detected by devices. The specificity of automatic detection is
very low, such that all previous studies until the RATE registry
have excluded any episode of atrial fibrillation detected by a
device less than 5 minutes in duration because they're
unreliable. A lot of them turn out to be false positive
detections. Our study was designed to evaluate whether even very
brief episodes of an atrial tachyarrhythmia might also be
associated with risk of clinical events and might or might not
warrant anti-coagulation.


 
Carolyn:
Ah, that's interesting, so you really helped to answer how brief
is "brief" when we need to talk about device-detected atrial
fibrillation. Could you expand on how you actually defined "short
episodes" here?


 
Steven:
Right. A short episode for the purpose of the RATE registry was
defined as an episode where the electrogram that we scrutinized
had both the onset and the offset of the episode within the same
electrogram tracing, so although we can't put a specific time
duration on it because that wasn't part of the criterion, it's
typically less than 20 seconds or so, although not always,
whereas a long episode was defined as an electrogram where either
the onset and/or the offset was not captured by the device memory
and therefore we don't know the duration. Some of those may not
have been very long, and some of those may have been extremely
prolonged episodes. That allows us to actually scrutinize the
electrogram. We looked at 37,530 individual electrograms using 8
teams of adjudicators, each with a physician and a field clinical
engineer from the device company so that we could actually say
definitively, "Yes, this was atrial fibrillation," or, "No, it
wasn't."


 
Carolyn:
This is the first study to really look under that 5-minute limit
of atrial tachycardias. What did you find?


 
Steven:
Well, we found that in contrast to prolonged episodes, short
episodes of atrial tachyarrhythmias were not associated with an
increased risk compared to those without atrial fibrillation of
pre-defined clinical events, including death from any cause,
heart failure, stroke, hospitalization for atrial fibrillation,
and a few other smaller events.


 
Carolyn:
This was over a 2-year follow-up period, is that right?


 
Steven:
The median follow-up was slightly less than 2 years, that's
right.


 
Carolyn:
What I really was struck with was also the second finding, the
propensity to develop longer episodes. Could you expand on that?


 
Steven:
We reasoned that in the clinic, one might be faced with a short
episode was we defined them, and then you don't know what's going
to happen for the next 2 years to bring to bear the results of
our study. We looked at if your first episode was short, what was
your likelihood over the full follow-up of the study of
progressing to longer episodes. About 50% of patients who had
their first episode as only a short episode progressed to a
longer episode over the full follow-up and therefore were in the
long category for the rest of the results. Half of them never got
a longer episode.


 
 
It was, as one might imagine, if you had your first short episode
very early in the study and had a longer follow-up, you were more
likely to end up in the long category, and if you had very
frequent short episodes, you were also more likely to end up in
the long category by the time the full follow-up was over with.
Having an initial short episode is not a guarantee that you're
never going to get a long episode and that you'll never acquire a
consideration of anti-coagulation.


 
Carolyn:
That was a very important message to me as well because it meant
that although I can be secure or reassured by these data for very
short episodes, I needed to look out for the development of
longer episodes, at least that's what your registry showed over 2
years of follow-up. I'm curious, Mark, what were your take-home
messages because that leaves us with a bit of a conundrum. What
do we do about anti-coagulation in these patients?


 
Mark:
I think this study is a big help to the practicing
electrophysiologist and practicing cardiologists. It's a very
ledger number of patients with a lot of episodes of afib. It's
reassuring to me that the shorter episodes of afib as defined by
the study, the individuals did not have a higher incidence of
stroke compared to those with no episodes, so it's reassuring and
very important clinically as I go through my practice.


 
 
I do look forward to more analyses and more data from this study
because although now we know that episodes less than 20 seconds
are in all likelihood not going to need anti-coagulation, we
still don't know about those from 20 seconds to 5 minutes.
Hopefully with more analysis of this study we'll get that answer
also.


 
Carolyn:
Steven, do you agree with that?


 
Steven:
We would love to have that. At first glance, you would think that
devices would give you all of the data you needed because after
all, they're monitoring the patient 100% of the time, but there
are difficulties with that because device memory is limited, and
you don't get electrograms that go on until the termination of
atrial fibrillation even if the device were accurate in
determining when that termination was because depending on how
the device was programmed and depending on whether it was a more
modern device later in the trial or earlier and had more or less
memory, it cuts off after a limited amount of time, and you don't
see necessarily how long the duration is.


 
 
Now, you can use device-based data. The device gives you its
estimate of how long the episode is, but those are not as
reliable as adjudicating the electrograms and actually looking at
them. Those data would be a little softer than the main results
if we get there.


 
Mark:
That was the data that was used for all of the other studies, was
[transassert 00:14:51]. It would be comparable to those other
studies. I still think it would be very important data that I'd
love to see.


 
Steven:
Okay, well, I agree. I think it would be very interesting to look
at that and a number of other things. We have a number of other
things we could do with this database. There are a number of
substudies that are in progress. For example, one interesting one
is there were some instances we found, because we actually looked
at these electrograms, there's something that we termed
"competitive atrial pacing," where the device will pace at times
when we as clinicians would not want to pace. For example,
pacemaker-mediated tachycardia would be an instance of that, but
then you can pace in the atrium inappropriately. There's a rhythm
called repetitive non-reentrant ventricular atrial systole,
which, although it's exotic to all of us, actually turned out to
be fairly common where there's pacing in the atrium that occurs
for various reasons when we want it to.


 
 
We actually saw instances where the device itself induced atrial
fibrillation. It wasn't that common, but we did see it. We have a
substudy that we're working on about the subjective competitive
atrial pacing to see how much of that there was and of what, if
any, consequence that was. That's one of the things that's been
done. Because we scrutinized these so carefully, we tracked
morphology and atrial rate at least as a crude estimate, and we
have those data, so we could actually evaluate whether if
something looks very, very rapid and disorganized as opposed to
more organized electrograms at a slower rate, did that make any
difference. We don't have any results for those analyses yet. I
agree with Mark that the intermediate durations would be
interesting to look at.


 
Carolyn:
I agree too, and I'm really grateful for you sharing those
thoughts. Very grateful for both of you for your time today. I
just have to congratulate you. I completely agree this paper
fills an important knowledge gap, and congratulations once again.


 
Steven:
Thank you very much.


 
Mark:
Thank you.


 
Carolyn:
Thank you for listening. You've been listening to Circulation on
the Run. Please tune in next week.