Circulation July 19, 2016 Issue

 


Speaker 1:
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. Joining me in just a
moment are Dr. James Gammie and Dr. Timothy Gardner to discuss
our feature paper this week describing the first-in-human
clinical experience with a novel transapical beating heart mitral
valve repair.


 
 
First, here are the highlights of this week's journal. The first
paper is from co-primary authors doctors Yoon, [Tsue 00:00:49],
and [Cha 00:00:50] as well as corresponding authors Dr. [Che
00:00:55]  and Dr. Kim from the Seoul National University
College of Medicine. These authors examine mechanisms underlying
diabetes-induced microvasculopathy, testing the hypothesis that
Notch signaling in endothelial cells may play an important role
in this condition.


 
 
The authors tested this hypothesis by inducing diabetes in
eight-week-old adult mice using intravenous streptozotocin. They
then modulated endothelial Notch signaling using chemical
inhibitors in both wild type and transgenic mice. Results showed
that the Notch ligand called Jagged-1 was markedly increased in
endothelial cells of diabetic mice. Using endothelial specific
Jagged-1 knocked down mice, they found that blocking Jagged-1
prevented diabetic microvaculopathy. Furthermore, using the
induceable endothelium-specific Jagged-1 knocked down mice,
blocking Jagged-1 even at four weeks after the establishment of
diabetic microvaculopathy could reverse the condition.


 
 
In summary, these findings show that diabetes induces Jagged-1
over expression and suppresses Notch signalling in endothelial
cells leading to diabetic microvaculopathy in adult mice. The
clinical implications are that dysregulated intercellular Notch
signalling may therefore represent a novel molecular target in
the treatment of diabetic retinopathy.


 
 
The next study by Dr. Smith and colleagues at the Leiden
University Medical Center in the Netherlands evaluated the
association between LDL cholesterol variability and four
cognitive domains at 30 months in the 4428 participants of the
prosper study.


 
 
Results showed that a higher LDL cholesterol variability was
associated with lower cognitive test performance for intermediate
and delayed memory-related tasks, selective attention, and
processing speed. Higher LDL cholesterol variability was also
associated with lower cerebral blood flow and greater white
matter hyperintensity load in an MRI substudy of 535 patients.


 
 
In addition to being independent of the mean LDL cholesterol
levels and of clinically overt cardiovascular diseases, these
associations were present both in the placebo and pravastatin
treatment [inaudible 00:03:43] of the prosper trial suggesting
that the findings did not mearly reflect pleiotropic effects of
statins or of nonadherence.


 
 
The study importantly provides the first observational evidence
that lipid variability, not just absolute or mean values, but the
variability, maybe of importance to neurocognitive function and
thus contributes while understanding potential pathways of
neurocogniticve decline.


 
 
The next study is by first author, Dr. [Huh 00:04:19], and
corresponding author, Dr. Ralph, from the Menzies School of
Health Research Charles Darwin University in Australia. These
authors aimed to investigate the long term outcomes from acute
rheumatic fever and rheumatic heart disease.


 
 
They achieved this aim by using linked data between the rheumatic
heart disease register, hospital data, and death register for
residents of the northern territory of Australia, and examined
1248 patients with rheumatic heart disease as well as 572
patients with acute rheumatic fever in the period 1997 to 2013.


 
 
The main findings were that in the first year after an acute
rheumatic fever episode, the incidents of progression to
rheumatic heart disease was 10 times higher than acute rheumatic
fever recurrence; 10% of rheumatic heart disease patients had
severe disease at diagnosis. The presence of comorbidities was
associated with higher incidence of rheumatic heart disease
complications and mortality. In particular, comorbid renal
failure and hazardous alcohol use accounted for 28% of the access
indigenous mortality.


 
 
These findings have global relevance for settings with high acute
rheumatic fever, rheumatic heart disease rates and really
emphasized the need for integrated chronic disease management
strategies for these patients.


 
 
The final paper is by first author Dr Bettencourt, corresponding
author Dr. Blankstein, and colleagues from Brigman and Women's
Hospital in Boston, Massachusetts. These authors sought to answer
the question what is the most appropriate score for evaluating
the pretest probability of obstructive coronary artery disease?


 
 
To answer the question, the authors compared the
Diamond-Forrester score with the two CAD consortium scores
recently recommended by the European Society of Cardiology, and
they did this in 2274 consecutive patients without prior CAD
referred for coronary CT angiography. CT angiography findings
were used to determine the presence or absence of obstructive CAD
defined as 50% or more stenosis.


 
 
Here's a refresher of the different probability scores. The
Diamond-Forrester score is calculated based on chest pain type
such as non-anginal, atypical or typical angina, gender, and age.
The first CAD consortium model score called CAD consortium basic
is also based on these factors, but was developed using more
advanced statistical modeling strategies which were not available
when the Diamond-Forrester model was derived. Additionally, the
population had a lower prevalence of disease than the original
Diamond-Forrester derivation cohort.


 
 
The second CAD consortium score called CAD consortium clinical
included the same characteristics as CAD basic, but also included
the following clinical risk factors; diabetes, smoking status,
hypertension, and dyslipidemia. Moreover, the presence of typical
chest pain was weighted less in diabetics compared to
nondiabetics in the CAD clinical score.  Results showed that
among symptomatic individuals referred for coronary CT
angiography, the CAD consortium clinical pretest probability
score demonstrated improved calibration and discrimination for
the prediction of obstructive CAD compared to the
Diamond-Forrester classification.


 
 
Driving home the clinical implications of this, the authors
applied these observed differences in pretest probability of
obstructive CAD to guidelines-based patient management algorithms
and projected that the use of the newest score could decrease the
proportion of individuals in whom testing would be recommended
and increase the yield of diagnosing obstructive CAD.


 
 
Those were the highlights of these weeks issue. Now, for our
feature paper. Our feature paper today is about the
first-in-human clinical experience with the transapical beating
heart mitral valve repair using a expanded
polytetrafluoroethylene chordal insertion device. We're really
lucky today to have the first and corresponding author, Dr. James
Gammie from the University of Maryland Medical Center as well as
Dr. Timothy Gardner, associate editor from Christiana Care Health
System to discuss this exciting paper. Welcome, both of you.


 
Tim:
Thank you.


 
James:
Thank you.


 
Speaker 1:
James, may I start with you? What an exciting title, a
first-in-human experience, and this is really sounding very
reminiscent of our experience with TAVR and aortic stenosis
valves. Could I ask you, with so many exciting things, what is it
about the results that excited you most?


 
James:
This is an exciting project in that we believe it affords a new
treatment option for patients with degenerative mitral
regurgitation. We believe that this is a less invasive way of
achieving surgical grade reduction of mitral regurgitation. This
is a project which has involved a great number of people on our
team both within the university and then within Harpoon Medical,
as well as our colleagues in Europe to bring this device from an
idea which was asked more than a decade ago into a clinical
experience.


 
 
It really rose out of our recognition in particularly my own
practice that virtually, every patient with degenerative mitral
regurgitation could be fixed with ePTFE or Gore-Tex neo-chords,
and the question became how can we place neo chords on a
prolapsed mitral leaflets without doing open heart surgery?


 
 
We begin working on that in the laboratory a number of years ago
and went through a variety of prototypes, and ultimately, came up
with this idea where we could use a 3 millimeter shafted
instrument with a specially designed wrap of Gore-Tex on a
21-gauge needle such that we could land on the underside of the
mitral leaflet, deploy device, and create a specially designed
knot on the atrial surface of the leaflet, and that would anchor
the ePTFE on the leaflet. We could repeat that a few times
transapically and then adjust the length of those chords in real
time using transesophageal echo guidance.


 
 
We got this to work in the laboratory and we had hoped that we
would have some modest success in humans, but we've been quite
pleasantly surprised that it has just worked and we've outlines
this initial clinical experience in the manuscript.


 
Speaker 1:
First of all, I'd just like to pick up on the point that this is
degenerative mitral regurgitation, so this is limited to the
primary mitral regurgitation, not secondary?


 
James:
That's correct and we know that right now, at least in North
America, that two-thirds of mitral valve operations are done for
degenerative disease. That's correct.


 
Speaker 1:
I think a lot of the audience out there is going to be wondering
how this new technique compares to the MitraClip. Could you tell
us a little bit more about that?


 
James:
I do MitraClip as well, so I think I'm well positioned to comment
on the differences. The Harpoon device right now is still in
operation. It does require a small one or two-inch incision. We
anticipate it's going to be a thoracoscopic approach in the very
near future and then, beyond that, we would hope to extend it to
a transcatheter approach. That's one difference.


 
 
The MitraClip now is certainly across the world. It's used
predominantly for functional mitral regurgitation. In our own
experience, it seems to work best for functional mitral
regurgitation and as you know, there are anatomic limitations for
MitraClip in degenerative disease. The MiraClip replicates the
LCRA surgical approach and I think what we've learned from all
the less invasive approaches to treat mitral valve disease is
that we have to respect what we've learned from our surgical
experience, and we know that the LCRA approach works best when
it's combined with an annuplasty ring, and certainly, the
MitraClip, again, is mostly this perfunctional MR.


 
 
Another point I'd bring up is that the experience with MitraClip
has been that when you place a MitraClip, you get a fairly strong
fibrous reaction and in most of the series, it's not been
possible to then go back and surgical repair the valve, but you
have to do a replacement because you've compromised the leaflets.
Our own approach were simply putting Gore-Tex sutures in the
leaflets and we believe that one advantage is that we're not
burning any bridges, and that you can go back and do an open
repair of you had to.


 
 
In our experience, you asked about our results, we had great
results in 10 out of 11 of our patients. One patient did require
a reoperation. Actually, one of the chords had come untied on the
surface in that patient. We were able to go ahead and do a repair
and we saw as we had anticipated it based on our animal
experience, there was not much compromised to the leaflets.


 
 
One of the advantages of our approach is that we can titrate the
length to the Gore-Tex chords to optimize the amount of
coaptation and maximize the quality of the repair, and that's
something that we can't do an open cardiac surgery, and one of
the challenges of mitral valve repair is that you have to figure
out how long to make those chords while the heart is arrested and
placid, and that's one of the challenges in why mitral valve
repair is certainly some degree of an art to doing that.


 
 
What we've found is that the imager is incredibly important, and
so we've teamed up with our echocardiography colleagues, and they
really provide essential input into the procedure, and it's done
not looking directly at the valve, but looking up at the screens.
I think as surgeons, with this procedure, we're moving more into
almost becoming interventionalists.


 
Speaker 1:
Thank you, James. That was so exciting. Tim, I have to bring you
into this now. Now that James has said they're becoming like the
interventionalist. Back to my original comment of TAVR and aortic
stenosis, are we witnessing history in the making now? You
invited an editorial by Dr. Michael Mack and his title was very
provocative, Transcatheter Treatment of Mitral Valve Disease. Is
it deja vu all over again? What are your thoughts?


 
Tim:
I think this is an exciting report and I think that this is the
wave of the future. I agree completely with Michael Mack that we
are beginning to see interventions for mitral valve disease that
are effective, less invasive, in some instances catheter based,
but this is just the beginning. In fact, mitral valve disease is
somewhat more complex even than aortic stenosis, but this type of
experience and the ingenuity and the technical prowess, and the
ability to do this minimally, invasively, and so on really
portend a whole new era.


 
 
I agree with Jim. This is sort of the common ground between the
interventional structural cardiologist and the surgeon, and we're
becoming even more entwined, more collaborative, and more
mutually supportive. We are in a new era and I think over those
next decade or so, we're going to see this and similar, and even
different procedures tried and proven to be useful for the
variety of mitral valve disorders that we encounter. Perhaps the
era of the full sternotomy for fairly straightforward, single,
focused operations will become something of a thing of the past.


 
Speaker 1:
That's beautifully put. James, with that comment, what are the
next steps?


 
James:
As we said in the manuscript, this isn't barely experience and
we're continuing to learn as we move [inaudible 00:17:07] to the
clinical arena. We are currently in the midst of a CE Mark trial
in Europe. We rolled it out to eight separate centers. As we
approve clinical experience, we will learn more about precisely
which patients work best with this approach and we will accrue
longer term data. We now have a number of patient out to a year
with stable results and so, as the numbers go up, we'll do that,
and then we anticipate a randomized trial in the United States in
the early to mid portion of 2017 where we'll compare this
approach to conventional open cardiac surgery.


 
Speaker 1:
That's fantastic. Thank you so much to both of you, gentlemen,
for joining me on our podcast today.


 
Tim:
Thank you.


 
James:
Thank you.


 
Speaker 1:
You've been listening to Circulation on the Run. Thank you for
joining us this week and don't forget to tune in next week.