Circulation May 16, 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.
Carlolyn Lam, associate editor from the National Heart Center,
and Duke National University of Singapore. What's the link
between DPP4 and aortic valve calcification? Well, to find out,
keep listening because we'll be discussing this and an important
new paper right after these summaries.


                               
The first original paper in this issue tells us that high
sensitivity Troponin I, may have a role in personalizing
preventive strategies in patients with Type II Diabetes. Dr.
Cavender and colleagues from University of North Carolina, Chapel
Hill, sought to describe the relationship between changes in high
sensitivity Troponin I and cardiovascular outcomes in the EXAMINE
phase 3B trial, which was designed to evaluate the cardiovascular
safety of alogliptin. The current analysis was restricted to
patients, randomized 30 days or more after the qualifying acute
coronary syndrome event, and high sensitivity Troponin I was
measured using the Abbot Architect Assay at baseline and six
months.


                               
The authors found that high sensitivity Troponin I was detectable
in the vast majority - 93% of patients with Type II Diabetes,
stabilized within 30 days after acute coronary syndrome. One in
six of these patients had high sensitivity Troponin I levels
above the 99th percentile upper reference limit. High sensitivity
Troponin I had a strong graded relationship with the incidence of
subsequent major cardiovascular events.


                               
Changes in high sensitivity Troponin I as small as two to six
nanograms per liter over six months, were associated with a
heightened risk of adverse outcomes. Particularly cardiovascular
death and heart failure. Alogliptin neither increased nor
decreased the risk of cardiovascular events in a high risk cohort
of patients with elevated high sensitivity Troponin I levels.
These findings therefore imply that serial measurements of high
sensitivity Troponin may have a role in preventive strategies,
either by intensifying or prolonging therapies in patients at
high risk or reducing or shortening therapies in patients at low
risk of cardiovascular events.


                               
The next paper describes the effects of Pioglitazone on cardiac
outcomes after ischemic stroke or transient ischemic attack in
patients with insulin resistance without diabetes in the IRIS
trial, which stands for Insulin Resistance Intervention after
Stroke. As a reminder, the IRIS trial compared the effects of
Pioglitazone with placebo on major cardiovascular events after
stroke or transient ischemic attack, in patients without diabetes
but who had evidence of insulin resistance. And it showed that
Pioglitazone improved insulin resistance, prevented diabetes,
improved CRP and reduced fatal and non-fatal stroke or myocardial
infarction.


                               
In the current paper, by Dr. Young and colleagues from Yale
Cardiovascular Research Center in New Haven, Connecticut, the
authors performed a secondary analysis of IRIS and examined the
effect of Pioglitazone on acute coronary syndromes, mainly
myocardial infarction or unstable angina. They found that
Pioglitazone reduced the risk of these events by 29%, with
benefit emerging after two years of treatment. Furthermore,
Pioglitazone reduced the incidence of Type I myocardial
infarction with a neutral effect on Type II myocardial
infarction. In summary, among patients with insulin resistance
without diabetes, Pioglitazone reduced the risk of acute coronary
syndromes after a recent cerebrovascular event, and may serve as
a useful secondary prevention therapy in addition to statins,
aspirin, and other established treatments.


                               
The next study tells us that immune complexes may be an important
biomarker in the risk stratification of Antiphospholipid
Syndrome. Now recall that Antiphospholipid Syndrome is
characterized by recurrent thrombosis in patients with
Antiphospholipid predictive antibodies. However, the predictive
value of the presence of Antiphospholipid auto antibodies is low.
And new markers are needed to identify carriers at higher risk.


                               
In the current study by Dr. Serrano and colleagues from Madrid,
Spain, the authors performed a historical cohort follow up study
based on the Magnum 12 plus 12 cohort, that included all patients
who had received a kidney transplant in their hospital in a 12
year period from 2000 to 2011. Sera used for the analysis were
collected in the 24 hours before the kidney transplant surgery,
and used to measure circulating immune complexes of
immunoglobulin A bound to beta II glycoprotein I.


                               
The authors then investigated the possible association of these
immune complexes with thrombosis, graft thrombosis and graft loss
in the six months following kidney transplant. They found that in
patients with the immunoglobulin A isotope antiphospholipid
antibodies, the presence of circulating immune complexes of
immunoglobulin A bound to beta II glycoprotein I, pre transplant,
was associated with acute thrombotic events. Patients positive
for the immune complexes had a much higher risk of developing
post transplant thrombotic events, and higher risk of graft
thrombosis mediated graft loss. On the other hand, complex
negative patients had the same thrombosis risk as the control
population. These findings imply that treatment to prevent
thrombosis should focus mainly on the immune complex positive
patients in this setting.


                               
The final paper addresses the issue that public reporting of PCI
Outcomes may create disincentives for physicians to provide care
for critically ill patients, particularly at institutions with
worse clinical outcomes. In this study from first author, Dr.
Waldo from the VA Eastern Colorado Health Care System in Denver,
Colorado, corresponding author, Dr. Yeh from Beth Israel
Deaconess Medical Center in Boston, Massachusetts, and
colleagues. The authors used state reports to identify 31 out of
86 hospitals that were recognized as negative PCI outliers in two
states: Massachusetts and New York, from 2002 to 2012.


                               
They sought to evaluate the procedural management and in hospital
outcomes of patients treated for acute myocardial infarction
before and after a hospital had been publicly identified as the
negative outlier. They found that outlier facilities were larger,
treating more acute myocardial infarction patients, and performed
more PCI's than non outlier hospital. The rates of percutaneous
revascularization increased similarly at outlier and non outlier
institutions after report of the outlier status. After outlier
designation, the in hospital mortality declined at the outlier
institutions to a greater extent than was observed at the non
outlier facilities. Thus, public reporting of outlier status may
prompt outlier facilities to improve case selection, and employ
systems improvements that optimize patient care, and improve in
hospital mortality among patients with myocardial infarctions.


                               
We are going to have such a fun discussion in today's feature
paper. Have you ever wondered what does dipeptidyl peptidase-4,
or DPP4 have to do with aortic valve calcification? Well, you're
about to learn, because in today's paper we actually learn that
DPP4 inhibitors, which you might recognize from diabetes, you
know drugs such as sitagliptin, could serve a potential
therapeutic target in aortic valve disease. To tell us about it
and discuss it, we have corresponding author, Dr. Jae-Kwan Song]
from Asan Medical Center in Seoul, South Korea, as well as Dr.
Thomas Eschenhagen, Associate Editor from University Hospital
Hamburg Eppendorf in Germany. Welcome, gentlemen.


Dr. Jae-Kwan
Song:         Hi.


Dr. Thomas
Eschenhagen:           
Hi.


Dr. Carolyn
Lam:              
Fascinating paper. I have to congratulate you first and foremost,
but please tell us, what inspired you to look at DPP4 in aortic
valve disease.


Dr. Jae-Kwan
Song:         Yeah,
actually as a clinician, I think there is two issues. One is the
prevalence of calcific aortic valve disease is increasing rapidly
in the developed and also developing countries. The second
important issue is that we do not have effective medical
treatment option. So I will say that the medical treatment of
calcific aortic valve disease is a typical example of unmet
clinical needs to serve this kind of troubled scientific issues,
our team have focused on the reciprocal interaction between
endothelial cells and interstitial cells. Because this potential
mechanism was well reported by other investigators that the
interaction between two cells are very critical for maintaining
aortic valve tissues. So first we started with Enos knockout
mouse, to go over what's going on in the aortic valve in the
models. In the human tissues in patient with calcific aortic
valve disease, we have found that DPP4 is specifically activated.
That's the beginning of our study.


Dr. Carolyn
Lam:              
Could you please explain to those of us who don't do basic
science research everyday, I mean, your study involves tissues
both from humans and mirroring models. Could you explain it very
simply what you did and what you found?


Dr. Jae-Kwan
Song:         Yes, in the
Enos Knockout mouse, we have found that those mouse showed very
strong calcification process compared to the live animals. What
is the mechanism of this enhanced calcification in this mouse?
And we found that the loss of endothelial  function is
critical, and then we found that DPP4 is actively involved in the
calcification process. The first test we have done is the
isolation of developed interstitial cells. And then we focused on
osteogenic transformation over this valvular interstitial cell
both in the Enos Knockout mouse, and the human developing
interstitial cells. So we have found that the endothelial
dysfunction activates the DPP4 activity in these tissues, which
resulted in the increase osteogenic transformation of developed
interstitial cell. So that's the beginning of our observation.


Dr. Carolyn
Lam:              
And could you describe what you did subsequently to prove the
whole mechanism?


Dr. Jae-Kwan
Song:         As you know
the DPP4 has many substrates including many peptides involved in
glucose metabolism, so the hardest part of our study is what is
the molecule target, or associated with DPP4 in the pathologic
process of calcification in developing interstitial cells. We
tested many different substrates known to the potential targets
of DPP4, and we have found specifically insulin-like growth
factor-1 (IGF-1) is the key proponent of all this process. With
further study, we found that the DPP4 cleaves or inactivates or
decrease IGF1 activity in the valvular interstitial cell, and in
the normal status IGF1 is a very critical to protect osteoblastic
transformation of valvular interstitial cell. We have found that
the DP4 and IGF1 exercises key therapeutic target, and the key
molecules involved in valvular calcification. As you know we do
have a DP4 inhibitors, which were successfully clinically to
reduce the diabetes control. So it's very easy to test the DP4
inhibitors in animal models. Both in the Enos Knockout mouse, and
we also developed in the calcific aortic valve disease using some
treatment, including Vitamin D and hypercholesterol and diet the
in vivo experiment showed that [inaudible 00:13:58] inhibitors
effectively prevented the development of calcification and
prevented the development of calcification and prevented the
developement of calcific aortic disease. This the main finding of
our study.


Dr. Carolyn
Lam:              
That is so fascinating, and really especially what you just said,
that sitagliptin in this rabbit model prevented calcific aortic
valve disease with the concurrent increase in plasma IGF1 levels
in line with the DPP4 inhibition. That is just such a beautiful
piece of work, congratulations. And congratulations Thomas on
managing such a nice paper. Take us under the hood about the
discussions that happened with the editors. Surely you recognized
the translational impact. What do you think? Is it time to
reposition DPP4 inhibitors?


Dr. Thomas
Eschenhagen:           
We and the reviewers like the paper because first of all it
describes a new, interesting biological mechanism. If we are
done, and we like that it uses human samples, but also this
treatment in two different animal models. This together, really
makes it a strong paper, we've found perfectly suitable for
Circulation. As you said Carolyn, the translation perspective is
fascinating. Obviously it's very early days. There is no specific
evidence yet from patients. But that could, in patients, take
actually very very long. Even the big studies already been done
with sitagliptin and other DPP4 inhibitors, that don't show a
signal in this direction yet, but I would say that could still
happen, and maybe in the long term, all of the cardiologists
putting all this stuff in German it's call TAVS, in America it's
called TAVR does not work anymore, obviously. That's just the
speculation.


                               
But it gives a very interesting signal, and this study certainly
should stimulate research in humans and do some prospective
studies in patients.


Dr. Carolyn
Lam:              
Yes indeed. If I may ask, Jae-Kwan, do you have plans for further
steps?


Dr. Jae-Kwan
Song:         Yeah, we
are expecting some [inaudible 00:16:06]. The first process with
proof of concept study as you know is DP4 inhibitors have been
actually been used for the diabetic controls, so we may have a
patient cohort who also underwent [inaudible 00:16:22]
echocardiogram [inaudible 00:16:23] while without medication. The
analysis of those later can be used for proof of concept study.
But we are challenging issues that although many drugs are
classified as a DP4 inhibitors, we should really focus on the
tissue distribution on these drugs, specifically on the cardiac
issues. It may be possible that the different drugs have a
different tissue distribution even after all our medication. The
second critical issue is what is the actual dose of these drugs
to prevent calcific aortic valve disease. Usually these drugs are
used for diabetes control. We may need different lab results of
these drugs for different critical indications. So that's the two
important issues to be solved.


Dr. Carolyn
Lam:              
That's wonderfully put, and I couldn't agree more. Thomas, could
we switch tracks a little bit. Because now that I have you
online, and you're the first time joining us on the show too,
tell us a little bit more about what it's like as an associate
editor really looking at these pre clinical data, being able to
parse out what you think has translational value, and especially
for circulation. We have a very strong emphasis now on clinical
translation. Share some of your thoughts there on how it's been
for us.


Dr. Thomas
Eschenhagen:           
It's been a great experience. I do have some experience with
other journals as an associate editor, or being on an editorial
board. But I have to say circulation is really quite unique. I
think it's a very strong group of people. I'm amazed by the level
of knowledge and also the level of engagement of the other
editors and associate editors, in every single paper. What's also
really rewarding is the overall quality of papers being submitted
to circulation, it's really great. A lot of papers are not only
presenting some beautiful, basic science, but also this
translational perspective, that's actually what we are looking
for. So very solid, exciting scientific work in cells, animals,
but always some link, either some materials from humans or a good
link to a translation perspective. That's the perfect paper for
circulation and I have to say we get quite a bit of them, and
it's sometimes even difficult to pick the ones we really like.
But it's great, it's really been a lot of fun.


 Dr. Carolyn
Lam:             
This is actually one of the purposes of this podcast. It's hoping
to share with our readers, with our listeners, what happens at
these editor discussions because it's so interesting, I just wish
everyone could listen to all the science and the clinical
translation that we discuss. Thank you very much for sharing your
thoughts today, both Thomas, and Jake Won, beautiful work. We're
very proud to be publishing this work in circulation.


                               
Thank you listeners for joining us this week. Don't forget, tell
all your friends about this podcast, and tune in again next week.