Circulation October 10, 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.


                                               
We know that excessive sedentary time is bad in terms of health
outcomes, but does it matter how that sedentary time is accrued,
whether in short or long bouts? Today's feature paper gives us
some answers. More soon, right after the summary of this week's
journal.


                                               
The first original paper in this week's journal provides insights
into the mechanisms underlying neointima formation in arterial
restenosis. Co-first authors, Dr. Cheng and Shi, corresponding
author Dr. Li from Wuhan University in China, and their
colleagues, performed an elegant series of experiments in which
they demonstrated that interferon regulatory factor 4, or IRF4,
which is a member of a family of key, innate, immune regulators
known to play a role in cardiometabolic disease, actually
protects arteries against neointima formation.


                                               
They further probed the mechanism underlying this protective
effect and found that IRF4 promoted the expression of
Krüppel-like factor 4 by directly binding to its promoter.
Genetic over-expression of Krüppel-like factor 4 in smooth muscle
cells reversed the neointima promoting effect of IRF4 ablation.
Whereas, ablation of Krüppel-like factor 4 abolished the
protective function of IRF4, thus indicating that the protective
effects of IRF4 against neointima formation were Krüppel-like
factor 4 dependent.


                                               
These findings suggest that the previously undiscovered IRF4
Krüppel-like factor 4 axis plays an important role in vascular
proliferative pathology and thus may be a promising therapeutic
target for the treatment of arterial restenosis.


                                               
The next paper highlights that high-spacial resolution in gene
expression signatures can reveal new regulators, genetic
pathways, and transcription factors that are active in
well-defined regions of the heart.


                                               
Now we know that traditional genome-wide transcriptome analysis
has been disadvantaged by the fact that the signals are derived
from tissue homogenates. Thus, the authors of this current paper,
including Co-First authors Dr. Lacraz and Junker, corresponding
author Dr. Van Rooij from University Medical Center Utrecht in
the Netherlands used tomo-seq to obtain genome-wide gene
expression signature with a high spacial resolution, spanning
from the infarcted area to the remote areas to identify new
regulators of cardiac remodeling.


                                               
Using this technique, they identified SOX9 as a potent regulator
of cardiac fibrosis. In vivo loss of SOX9 reduced the expression
of many extracellular matrix genes, which coincided with a
blended cardiac fibrotic response upon ischemic injury.


                                               
These data therefore were able to unveil currently unknown
relevance of SOX9 as a key regulator of cardiac fibrosis, thus
underscoring that tomo-seq can be used to increase our
mechanistic insights into cardiac remodeling, and to help guide
the identification of novel therapeutic candidates.


                                               
The next paper reports the primary results of the effect of
ferric carboxymaltose on exercise capacity in patients with iron
deficiency and chronic heart failure, or EFFECT-HF study, which
is a randomized control trial of intravenous ferric
carboxymaltose, compared to standard of care on the primary end
point of change in peak Vo2 from baseline, to 24 weeks in
patients with symptomatic, chronic heart failure with reduced
ejection fraction and iron deficiency.


                                               
In this report from Dr. van Veldhuisen from University Medical
Center Groningen and colleagues, intravenous ferric
carboxymaltose was shown to significantly increase serum ferritin
and transferrin saturation. At 24 weeks, peak Vo2 had decreased
in the control group, but was maintained in the group receiving
intravenous ferric carboxymaltose.


                                               
Although a favorable effect on peak Vo2 was observed with ferric
carboxymaltose, compared to standard of care in the primary
analysis, this effect was highly sensitive to the imputation
strategy for peak Vo2 among patients who died.


                                               
They also reported that patient's global assessment and
functional class, as assessed by New York Heart Association,
improved on ferric carboxymaltose compared to standard of care.


                                               
Whether ferric carboxymaltose is associated with an improved
outcome in these high risk patients, deserves further study.


                                               
The final study provides important long term clinical data to
guide lead management decisions in patients with cardiac
implantable electronic devices.


                                               
Dr. Pokorney from Duke University Medical Center in Durham, North
Carolina, and colleagues, analyzed over 6,000 Medicare patients
and found that device extraction was associated with a lower
adjusted five year infection rate, compared with a cap and
abandon strategy. There was a lower absolute five year mortality
with extraction, but after adjustment there was no association
between extraction and a lower five year mortality.


                                               
In summary, therefore, elective lead extraction for
non-infectious indications in this Medicare cohort had similar
long term survival, but lower risk of device infections at five
years, compared to capping and abandoning leads.


                                               
Patient and provider preferences are critical to decision making
when considering extraction versus capping and abandonment of
leads.


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


                                               
For today's feature discussion, we are talking about sedentary
time and a metabolic risk of having too much of it. But, today's
paper is so interesting because it tells us that it's not just
the total amount of sedentary time that may matter, but how we
accrue the sedentary time. Very, very novel concept in my point
of view and I'm so pleased to have the first and corresponding
author of this paper, Dr. Keith Diaz from Columbia University
Medical Center with us, as well as Associate Editor from Johns
Hopkins, Dr. Wendy Post.


                                               
So pleased to have you both. Keith, could we just dive right into
it? Tell us what population you were looking at, and what you
found.


Dr. Keith
Diaz:                   
Sure, so we were studying a population of participants enrolled
in the Hispanic Community Health Study, so it's a US populations
of over 16,000 Hispanic adults. And essentially what we found was
that sitting for prolonged bouts, so sitting for one, two hours
at a time, was associated with poor glucose regulation.


Dr. Carolyn
Lam:              
Well, yikes. I've actually been sitting for a few hours in a row
right now, actually. I think these results are phenomenal, but
could you maybe expand a little bit on the details, like how long
is too long? And, how often a break needs to happen for you to
see differences in the metabolic risk?


Dr. Keith
Diaz:                   
It's a good question and, to be honest, we don't know. I think
that's where the research needs to head, but right now it seems
to be that taking a break every 30 to 60 minutes could be
beneficial. I think that's what we've found thus far.


Dr. Wendy
Post:              
Keith, we were really excited to get your paper in. I think
everyone on the Associate Editorial Board was especially
interested in it because we can all relate. As Carolyn said,
she's been sitting for a long time and when we have these
meetings we have two hour meetings at a time and maybe we need to
start saying that in the middle we should all stand up and take a
break. So we can all relate to this.


                                               
But I think one the biggest questions that we had related to data
itself, was the association between the total sedentary time and
the sedentary bout duration. Maybe you can tell us a little bit
more about those correlations in the interaction and tell us also
how you also measure sedentary bout duration and total sedentary
time in this observational cohort.


Dr. Keith
Diaz:                   
Sure, so I'll start with that latter question. So, we measured
sedentary time [inaudible 00:09:32] subjectively. So we actually
used an activity monitor called an accelerometer to see how
sedentary they are. And how we quantified sedentary bouts is we
just looked at how long consecutively a person sat without
moving. That was considered sedentary bout. In terms of
correlation, what we found is that there are very closely linked.
So, people who sit for long hours during the day for total
volume, also sit in long bouts. And so what we wanted to do was
try to figure out and piece apart, which one is more important?
When we're trying to ... If we're thinking about guidelines and
what we should be doing about our sedentary time, is it important
to reduce our volume or interrupt our bouts? And so what we found
is that they're not independent, and that they're in many ways
synergistic. And that the association of prolonged sedentary
bouts with glycemic biomarkers varied according to how much total
volume you sit and vice-versa.


Dr. Wendy
Post:              
Can you expand a little bit more on that? So tell us about the
interaction that you found between sedentary bout duration and
total sedentary time.


Dr. Keith
Diaz:                   
Sure, so we did find that there was a specifically significant
interaction between the two variables and so what we tried to do
is actually categorize people as to whether they were high for
both characteristics or high for just one of them. And so what we
found was that those participants who are high for both, so they
had high volume and sat in long bouts, they had the worst glucose
regulation, and that those individuals that were high for just
one of the characteristics had a little bit better glucose
regulation. And so really what we thought the take home message
was when thinking about how do we improve our sedentary behaviors
is that it's targeting both. It's not sitting for large volumes
during the day, but also making sure to take frequent breaks
every 30 or 60 minutes.


Dr. Wendy
Post:              
And tell us about the glucose measures that you included in your
study.


Dr. Keith
Diaz:                   
Yep, we had a couple glucose measures. One we had people do a two
hour glucose tolerance test, so they took a glucose drink and
then we measured their blood sugar levels two hours after having
that drink. We also measured their H1Ac levels as well as their
fasting glucose and fast to link insulin measures from which we
can then derive measures of something called HOMA IR, which is a
measure of insulin resistance.


Dr. Wendy
Post:              
And the associations that you saw were primarily with the HOMO IR
and the two hour glucose levels but less with the hemoglobin A1c?


Dr. Keith
Diaz:                   
Correct.


Dr. Wendy
Post:              
So it really appears to be that insulin resistance that's most
affected by the total sedentary time and sedentary bout duration.
Tell us about potential confounders and how you factored that
into your analysis.


Dr. Keith
Diaz:                   
Yeah, there was quite a number of potential confounders between
this relationship of sedentary behavior and glycemic biomarkers.
One of them in particular that we were concerned about most were
things like body mass index or exercise or physical activity
levels. And so we took a look at what we adjusted for those
confounders how the relationship changed. And what we did find
was that there was an attenuation and association between
sedentary behavior and the glucose markers, but there was also
... were still statistically significant. So suggestive that
maybe they're partly in the pathway of body mass index or
exercise but they didn't make the relationship go away. I should
add that we looked at a couple other confounders, we looked at
things like inflammation, C-reactive protein, as well as whole
bunch of other measures of cardiovascular risk factors. I'll stop
there.


Dr. Wendy
Post:              
And what about the fact that study is cross-sectional, are there
any caveats related to the study design that you'd like to point
out to the audience?


Dr. Keith
Diaz:                   
Yeah, I think that's an important point, that this is
cross-sectional, so by no means can we infer causality that
sedentary behavior causes glucose dysregulation, it's just purely
an association. So I think anyone listening to this podcast
should keep that in mind when reading this paper or listening to
this podcast.


Dr. Wendy
Post:              
So if you were writing the next set of guidelines what would you
recommend in terms of how you implement these findings into
guidelines? Not to imply that we think that these cross-sectional
observational data mean that we're ready to change guidelines
but, if these were replicated in randomized trial or some other
more objective data study design, how do you think we should use
these results to change our behaviors?


Dr. Keith
Diaz:                   
I think these guidelines point ... or, with the current
guidelines are, sit less, move more, where the guidelines that
came out from AHA in October of 2016. In part, they were not as
specific because we don't have quite the quality of guidelines or
data that we need for more qualitative guidelines, or
quantitative guidelines. I think if we're able to replicate these
data with [inaudible 00:14:10] or point us towards at least is,
also, that we should be interrupting our sedentary bouts. And so
what I'd like to see hopefully if we can replicate something I'd
like guidelines that say every 30 minutes or every 60 minutes of
sitting you should stand up and move. And hopefully with future
studies that are coming out that we can make them even more
specific and something along the lines of every 30, 60 minutes
you stand up and walk for 5 minutes or you just stand up for 1
minute. That's where I'd like to see the science head and I think
this study points us in the that direction of maybe we have to
start thinking about breaking up our sedentary bouts.


Dr. Carolyn
Lam:              
All right you guys, I don't know about you, but I am literally
standing up right now while I'm listening to you both. This is so
interesting and I love the way, Wendy, you reflected the robust
discussions we had as team when we were working through this
paper. Congratulations again, Keith, for just this remarkable
paper. Actually, maybe I could just ask, Wendy, what do you
think? What do you think our next steps that may need to get
these kinds of recommendations, perhaps into guidelines?


Dr. Wendy
Post:              
I think as was alluded to before, these are observational data so
they're important for hypothesis generation, but really to have
evidence that would lead to changes in guidelines maybe having a
randomized trial, where obviously you can't have very hard
outcomes, but randomized trials of some duration that could
potentially lead to changes and important outcomes, would then
maybe lead to changes in guidelines. But there isn't anything
that we would lose from trying to implement these kinds of
behavior, changes into our lifestyle since the downside and the
risk is pretty low. So even if they don't make the strongest
level of evidence at this point, I think we can still all be
mindful of this and so.


                                               
One thing that we've been trying to do in our preventive
cardiology group at Hopkins is trying to implement walking
meetings. In fact, I just had an email discussion with one of my
colleagues about meeting tomorrow and she said, "Well, where do
you want to meet?" And I said, "Well, why don't we go for a walk?
The weather should be nice." And so I think if we're all mindful
of trying to, not only increase our amount of physical activity,
but trying to limit the sedentary bout duration by being creative
and trying to change, sort of, long standing traditions of having
meetings sitting in an office, then that could be helpful.


                                               
So, just something for our audience to think about as well.


Dr. Carolyn
Lam:              
That's brilliant. You know, the one thing that I was thinking,
though, just thinking about the reception of these data in my
country, in where I practice, in Asia. This was a purely Hispanic
or Latino population. I suppose there is a perception that that
population may be predisposed to cardiometabolic disease and so
on, and so you know, what's the applicability to us in Asia? So,
I'm really happy, particularly to hear how you've taken it on. I
mean, it's a simple thing, why not, right? Just to be more
active. There's surely can't be something wrong with that. What
do you think of that?


Dr. Wendy
Post:              
Totally, I think it's important to emphasize the unique nature of
these data and that they come from a Hispanic study, which is a
really important addition to our literature in epidemiology and
cardiovascular disease and certainly there are significant
differences in lifestyle among different communities within the
United States and across the globe, as you've experienced having
lived in different countries. And so, I think we need obtain more
data about how there might be differences based on various
traditions and different lifestyles, and try to target those who
are at greatest risk.


Dr. Carolyn
Lam:              
Keith, did you have anything to add to that?


Dr. Keith
Diaz:                   
Yeah, I think Wendy is right on and certainly I don't think we
have any reason to suspect that sedentary behavior acting
differently in Hispanics versus other populations, and so I still
think going forth with this notion that we all should be reducing
our sedentary behaviors is important to highlight.


Dr. Carolyn
Lam:              
Fantastic. Well, thank you both for a really wonderful
discussion. This is really cool, I think a lot of people will be
talking about this.


                                               
Listeners, you've heard it first, though, in Circulation on the
Run. Thank you for joining us today and don't forget to tune in
next week.