Jul 18, 2016
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.