Circulation July 25, 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 journal this week
features an in-depth review on transcatheter therapy for mitral
regurgitation, a very, very hot and interesting topic. You have
to listen on, coming up right after these summaries.


                                               
Our first original paper this week sheds light on the influence
of aging on aldosterone secretion and physiology. First author
Dr. Nanba, corresponding author Dr. Rainey and colleagues from
the University of Michigan in United States, examine the
relationship between age and adrenal aldosterone synthase in 127
normal adrenals from deceased kidney donors. The donors' ages
ranged from nine months to 68 years. The authors found that
adrenals from older individuals displayed less normal aldosterone
synthase expression and zona glomerulosa, and greater content of
abnormal foci of aldosterone synthase expressing cells.


                                               
Furthermore, older age was independently associated with
dysregulated and autonomous aldosterone physiology, in an
ancillary clinical study of subjects without primary
aldosteronism. This study therefore suggests that aging may be
associated with a sub-clinical form of aldosterone excess and
provides at least one potential explanation for age related
cardiovascular risk.


                                               
The next study shows, for the first time, that the chemokine
receptor, CXCR4, in vascular cells, limits atherosclerosis. The
CXCL12 and CXCR4 chemokine ligand receptor axis is known to
control cell homeostasis and trafficking. However, its specific
in atheroprotection has thus far been unclear. This is addressed
in today's study by first author Dr. During, corresponding author
Dr. Weber, and colleagues of The Institute for Cardiovascular
Prevention in Munich, Germany. In hyperlipidemic mice, the
authors showed that cell-specific deletion of CXCR4 in arterial
endothelial cells, or smooth muscle cells, marked the increase
atherosclerotic lesion formation. Mechanistically, CXCR4 axis
promoted endothelial barrier function through VE-cadherin
expression and a stabilization of junctional VE-cadherin
complexes. In arterial smooth muscle cells, CXCR4 sustained
vascular reactivity responses, and a contractile smooth muscle
cell phenotype. Whereas, CXCR4 deficiency favored the occurrence
of macrophage-like smooth muscle cells in atherosclerotic plaques
and impaired cholesterol efflux.


                                               
Finally, in humans, the authors identified a common allele
variant within the CXCR4 locus that was associated with reduced
CXCR4 expression in carotid RG plaques, and increased risk for
coronary heart disease. Thus, the study suggests that enhancing
the atheroprotective effect of arterial CXCR4 by selective
modulators may open normal therapeutic options in
atherosclerosis.


                                               
The next paper is the first to study the effects of rosuvastatin
on carotid intima-media thickness in children, with heterozygous
familial hypercholesterolemia. First author Dr. Braamskamp,
corresponding author Dr. Hutten, and colleagues from Academic
Medical Center Amsterdam in the Netherlands, study children with
heterozygous familial hypercholesterolemia aged 6 to less than 18
years, with LDL cholesterol more than 4.9, or more than 4.1
millimoles per liter in combination with other risk factors, who
received rosuvastatin for 2 years, starting at 5 milligrams once
daily, with uptitration to 10 milligrams for children aged 6 to
10 years old, or 20 milligrams daily for those aged 10 to 18
years old.


                                               
Carotid intima-media thickness was assessed by ultrasonography at
baseline, 12 months and 24 months in all patients and in
age-matched, unaffected siblings. Carotid intima-media thickness
was measured at 3 locations, the common carotid artery, the
carotid ball, and the internal carotid artery in both the left
and right carotid arteries. At baseline, the mean carotid
intima-media thickness was significantly greater for the 197
children with heterozygous familial hypercholesterolemia compared
with the 65 unaffected siblings. Rosuvastatin treatment for 2
years resulted in significantly less progression of increased
carotid intima-media thickness in children with heterozygous
familial hypercholesterolemia than in the untreated, or
unaffected siblings. As a result, there was no difference in
carotid intima-media thickness between the two groups after two
years of rosuvastatin. These findings, therefore, support the
value of early initiation of statin treatment for LDL cholesterol
reduction in children with heterozygous familial
hypercholesterolemia.


                                               
The final study highlights the therapeutic potential of a novel
alpha calcitonin gene-related peptide for the treatment of heart
failure. First author Dr. Aubdool, corresponding author Dr.
Brain, and colleagues from King's College London in United
Kingdom, tested the stable alpha analog of calcitonin
gene-related peptide in 2 models ... First, an angiotensin 2
infused mouse, and secondly, pressure overload cardiac
hypertrophy mouse model using suprarenal aortic ligation. They
showed that systemic colon injection of the alpha analog blunted
the angiotensin 2 induced rise in blood pressure, as well as the
vascular and cardiac remodeling, changes in water consumption,
and renal injury, that are normally associated with angiotensin 2
infusion. Furthermore, protective effects were also seen when
starting the alpha analog treatment, only during the last week of
the 2-week angiotensin 2 infusion, in other words, when
hypertension was already established. Finally, the alpha analog
preserved heart function, and diminished the degree of
hypertrophy and fibrosis in the aortic ligation model.


                                               
Thus, these results demonstrate the therapeutic potential of the
alpha calcitonin gene-related peptide pathway, and the
possibility that this injectable alpha analog may be effective in
cardiac disease.


                                               
Well, that wraps it up for this week's summaries! Now, for our
featured discussion.


                                               
For our feature discussion this week, we're talking about
trans-catheter therapy for mitral regurgitation, a very hot field
and a field in which there have been a lot of advances. To help
us break it down, and get right into the insights, the
challenges, and potential solutions, I am so pleased to have the
first author of this in-depth review paper, Dr. Paul Sorajja from
Minneapolis Heart Institute Foundation and Abbott Northwestern
Hospital, as well as Dr. Manos Brilakis, associate editor from UT
Southwestern, here with us today!


                                               
Paul, could I start with you, and just ask you first to give us
an idea of what we're talking about here when we talk about
mitral regurgitation ... There are different kinds, which are we
referring to, and what are the challenges involved in a
trans-catheter therapy for mitral regurgitation?


Dr. Paul
Sorajja:               
I think there are a number of challenges, I think the first thing
is that MR is often thought of as one disease, but it's really an
incredibly heterogeneous disease ... Broadly, we talk about
primary versus secondary MR, but the mitral valve is so complex,
with multiple different components, any one of which can disrupt
and cause MR. When we're talking about trans-catheter therapy,
it's often very easy, again, to think we could have one therapy
that could treat a simply insufficient valve, but it's way more
complex than that, and as a result, there have been many
different approaches that have been developed, adding to the
complexity of how we manage these patients.


Dr. Carolyn
Lam:              
Right, and in your paper, I loved the way you grouped them, very
logically, under those from mitral valve repair, and that for
mitral valve replacement ... And then, under repair, you grouped
it into leaflet versus targeting the LV ... Could you maybe give
us some top-line insights on these techniques?


Dr. Paul
Sorajja:               
Yeah, there are a number of different approaches that have
mechanistically gone after the different components through the
pathophysiology of MR, where there is leaflets, where there's
analysts, cords, or ventricular approach ... I think it's
somewhat simplistic to think of it that way, but as
catheter-based technology, we are technically limited by what we
can do from a catheter standpoint. I think it's inevitable to
think about these catheter technologies as eventually being
combined, rather than singular, in order to approach what
surgeons do in the OR.


Dr. Carolyn
Lam:              
Right, but then even going further, you spent quite a bit of the
paper talking about trans-catheter mitral valve implantation ...
So, replacing the mitral valve, that's really cool, could you
tell us a bit about that, and about that important issue brought
up about patient selection.


Dr. Paul
Sorajja:               
Yes, it's a very good point, I think in terms of trans-catheter
mitral replacement, I think that that's really where the future
is going to go ... The simple analogy is that people think that
it will follow the route of TAVR, but I think it will follow the
route of TAVR more quickly so, because when you look at how the
mitral valve is currently treated in the OR, sometimes, a lot of
the times, patients can end up worse. Whereas, a trans-catheter
solution actually, I think in terms of the safety margin,
actually will equate a degree of safety relative to surgery, if
it's done and developed correctly, as opposed to how TAVR's done.
I think for TAVR, it's been a number of years for our field to be
equivalent or superior to surgery, whereas I think with mitral, I
think there's a lot of potential for mitral to have equated a
degree of safety. As an example, in the Tendine Feasibility
Study, it was published this past January ... A high-risk
population, there was not a single procedure death, out of 30
patients ... And for these patients who would go to the OR with
an eject fraction of 30 to 40 percent, I think that's quite
remarkable.


Dr. Carolyn
Lam:              
Wow, that's really exciting indeed! Manos, you handled this
paper, and it's just so beautifully laid out ... That flow chart,
I just want to refer all our listeners to the flow chart in
Figure 7, that talks about maybe an approach that can be
considered. Manos, could you share some thoughts on how this
developed?


Dr. Manos
Brilakis:          
Yeah, absolutely, and obviously Paul is the expert on this, but I
think it's very important about this paper, and through
discussions with Paul and through the development of the paper,
is that there's more of a collaboration between the surgeons and
the interventionists. So instead, if it's additional style of ...
Or the interventionists are doing one thing and the surgeon is
doing another, I think the key to success in the mitral field is
working very closely together ... Many of those valves right now,
the percutaneous valves, are done through a cut down and a
typical approach, so working very closely to addressing the
anatomic components of the mitral valve problem is a big plus.


                                               
The other thing I think that is very important is the new
emergence of imaging, trying to understand whether the new mitral
valve is going to create issues with LVOT obstruction or not. I
think that's leading to a whole new understanding of when and how
patients are even candidates for this approach, and I think Paul
can elaborate more on this, but as things evolve, fewer and fewer
patients are going to be excluded from these new technologies.


Dr. Carolyn
Lam:              
Paul, would you like to take that? What do you think is happening
and will happen with patient selection?


Dr. Paul
Sorajja:               
There has been a challenge in current feasibility studies, in
terms of getting patients in, the anatomical restraints are
exactly what Dr. Brilakis has outlined. There's a certain
bulkiness and size to the valve, which essentially poses risk for
LVOT obstruction if the valve is too big ... As a feasibility
study that's still early, or a field that's still early in its
development, there's been a really conservative approach in terms
of patient selection to ensure that LVOT obstruction doesn't
happen. I think we're pushing the boundaries for that, and I
think we've learned a lot from CT imaging, in terms of predicting
LVOT obstruction, and I think the valves are also getting to be
shorter in profile, which makes it less likely ... But that is
definitely one of the limitations, and it's a limitation that
exists, not just for trans-cat therapy but also for surgical
therapy.


Dr. Carolyn
Lam:              
Right, and then maybe a question for both of you ... What do you
think the future is going to hold? What do we need to make this
more mainstream, and where do you think this will leave surgical
approaches? I know you said a combined approach, but maybe you
could elaborate a little bit more?


Dr. Paul
Sorajja:               
I do think, and I agree, I think Manos' point is spot on about
that ... This will have to be multidisciplinary, the surgeons and
cardiologists absolutely need to continue to work together,
that's what's led to the successful development of TAVR, and I
think that will be even more so for mitral, because the mitral
valve is just infinitely more complex, and we have a lot to learn
from the surgeons. But I think going forward, the collaboration
is going to be a requirement, and then the training is also going
to be a significant portion ... Putting in a mitral valve is much
more complex than putting in an aortic valve ... I think if
there's a safety margin that's demonstrated, I still think that
it will be more appealing and more rapidly adopted than aortic
disease.


Dr. Carolyn
Lam:              
Well, Manos?


Dr. Manos
Brilakis:          
No, I completely agree with Paul on that respect. I think, in my
mind, at least, an again, this is from an early standpoint, the
next big step would be to make it completely percutaneous, right
now, you still have to do the cut down, and it's a little more
invasive, although still safer than the completely open surgery,
but maybe having a complete percutaneous system would be the next
big step ... There's no question in my mind, as well ... And
watching very closely how Paul and the surgical team are handling
this, I think this is definitely the way for the future.
Sometimes, in TAVR, it's not as technically demanding, and you
don't really need to have too many people in the room, but for
this procedure, it's definitely more important to have everyone
in the room, and benefit from everyone's expertise.


Dr. Carolyn
Lam:              
Manos, could I switch tracks for a moment now, and ask you to
comment on the question that I get a lot ... You're an
Interventionist, you handle a lot of the interventional papers
for Circulation, and a lot of people are wondering, what makes
papers like Paul's ... What makes interventional papers something
that we would want to publish in Circulation? Could you share
some thoughts?


Dr. Manos
Brilakis:          
Absolutely, thanks Carolyn ... That's a big part, I think, of the
appeal of Circulation right now. We're really trying to
communicate to people that cutting-edge, clinical science is
actually at the heart and the core of Circulation, and clinical
content is what drives a lot of editorial ... Especially in
intervention, where particularly interesting and new,
cutting-edge technologies, new trials, observational studies ...
But essentially, things that are cutting-edge, and are going to
have a specific implication and impact in the way the field is
going ... And this is part of Dr. Sorajja's paper, showing where
the future lies in terms of trans-catheter mitral technologies,
but along the same lines, we love to have cutting-edge papers on
various aspects ... Coronary, peripheral, all aspects of
interventional cardiologies, as well as interventional imaging
... The goal, again is to make the submission easy, there are not
many honors requirements for submitting the papers, it's very
simple to submit, and there's an answer going out very quick, so
we're looking forward to receiving more and more interventional
papers on cutting-edge science.


Dr. Carolyn
Lam:              
Thank you so much for joining us today, and don't forget to tune
in again next week.