Circulation September 27, 2016 Issue

 


Dr. 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 in
Duke National University of Singapore.


 
 
Today we will be discussing the first multinational study looking
at per-cutaneous device closure of peri-valvular leaks, a topic
I'm certain you'll recognize as rapidly developing in cardiology,
but first, let me fill you in on the highlights of this week's
journal.


 
 
The first paper is a translational study telling us that when
transfusing stored red blood cells for hemorrhagic shock, cold
transfusing hemopexin and heptoglobin may be beneficial. This
study is from first author Dr. Graw, and corresponding author Dr.
Zapol and colleagues from the anesthesia center for critical care
research at Massachusetts General Hospital and Harvard Medical
School.


 
 
These authors reasoned that erythrocytes undergo progressive
deleterious changes during storage. Such that, the transfusion of
long-stored, packed red blood cells increases plasma levels of
cell-free hemoglobin and heme. These are toxic breakdown products
of hemolyzed erythrocytes.


 
 
Now, mammals usually synthesize the scavenger proteins:
heptoglobin and hemopexin, which bind these toxic extracellular
hemoglobin and heme, respectively. The authors therefore, tested
the concept of cold transfusion of heptoglobin and hemopexin
along with stored red blood cells in their murine remodel of
hemorrhagic shock.


 
 
They first showed that resuscitation with long-stored, packed red
blood cells produced a higher mortality, higher plasma hemoglobin
levels, hemoglobinuria, kidney injury and diffused tissue
inflammation, compared to resuscitation with fresh, packed red
blood cells. However, when resuscitating hemorrhagic shock with
stored red blood cells co-infused with either exogenous human
hemopexin or heptoglobin, there was an increased survival and
decreased tissue inflammation. Furthermore, co-infusion of
heptoglobin with the stored red blood cells, prevented
hemoglobinuria and kidney injury. These animal model data warrant
further assessment in clinical conditions of severe hemolysis.


 
 
The next study suggests that sickle cell disease, although
primarily a blood disease, may also be considered a vascular
disease. This is a paper from co-authors Dr. Ranque and Menet
from the University Paris Descartes in France, and describe
results from the CADRE study. That is, the heart arteries and
sickle cell study, which is the World's largest ongoing cohort of
sickle cell disease that prospectively recruited more than 3,700
patients with sickle cell disease and 950 healthy controls from
Cameroon, Ivory Coast, Gabon, Mali, and Senegal.


 
 
The authors found that mean carotid femoral pulse wave velocity
was lower in patients with sickle cell disease, compared to
controls and lower in specific hemoglobin phenotypes compared to
others. Augmentation index, corrected for heart rate, also
increased more rapidly with age in the patients with sickle cell
disease, compared to controls, and was higher in patients than in
controls. Both carotid femoral pulse wave velocity and
augmentation index were independently associated with the
glomerular filtration rate and osteonecrosis.


 
 
Augmentation index was also associated with stroke, pulmonary
hyper-tension and priapism. Whereas, carotid femoral pulse wave
velocity was also associated with microalbuminuria. These
findings really under-score the association between sickle cell
disease and vascular abnormalities and complications. The
prognostic value of these vascular indexes will be assessed
during the follow-up of these patients.


 
 
The next paper is a basic science paper suggesting that after
sudden cardiac arrest, normalizing calcium cycling, may be a
novel approach to improved post-arrest myocardial function. This
paper is from co-corresponding authors Dr. Woods, from the Palo
Alto Medical Foundation and Dr. Ashley from Stanford University
in California.


 
 
These authors developed a rodent model of cardiac arrest using
ECMO resuscitation. They used a genetically encoded calcium
sensor in a novel fiber optic catheter imaging system to observe
calcium-induced calcium release in-vivo before and after
resuscitation. They then isolated cardiomyocytes from this model
and assessed a mechanical load and calcium cycling
simultaneously, using the micro-fiber carbon technique.


 
 
The main finding was of potentiation of calcium-induced calcium
release in the post-arrest situation that began in-vivo and was
mediated by activation of the calcium calmodulin kinase 2 or
CaMKII. Since they also observed that oxidated stress and
aldehydic adduct formation were high post arrest, they further
tested a small molecule activator of aldehyde dehydrogenase type
2, known as Alda-1, which reduced oxidative stress, restored
calcium and c CaMKII homeostasis and improved cardiac function in
post-arrest outcomes in-vivo.


 
 
These findings are significant for their potential translational
application in post-sudden cardiac arrest, a condition which is
really known to have a high mortality.


 
 
The next study reports the results of the DOCTORS Study, standing
for Does Optical Coherence Tomography Optimized Results of
Stenting. This paper is from Dr. Meneveau from the University
Hospital Jean Minjoz and colleagues. The DOCTORS Study is the
first randomized control trial testing optical coherence
tomography via OCT guided PCI to standard fluoroscopy guided PCI
in 240 patients with non-ST-elevation and acute coronary
syndromes.


 
 
The first finding was that OCT results directly impacted
physician decision making, leading to a change in procedural
strategy in half of the cases in the OCT guided group. The
primary end-point of functional results of PCI, as assessed by
post-PCI, FFR, was modestly improved in the OCT guided group
compared to fluoroscopy alone. This improvement appeared to be
explained mostly by optimization of the stent expansion. The
benefit was obtained at the cost of a longer procedural and
fluoroscopy time and more contrast use, but without an increase
in peri-procedural myocardial infarction or kidney dysfunction.


 
 
These findings of the DOCTORS study add to the accumulating body
of evidence supporting a potential benefit of OCT to guide PCI
procedures in acute coronary syndrome. Additional prospective
studies with clinical endpoints are warranted. These issues are
discussed in an excellent accompanying editorial by Dr. Wijns and
Dr. Pyxaras.


 
 
This brings us to the end of our summaries. Now for our feature
paper.


 
 
Our featured paper today discusses a problem that we've actually
created and that is para-valvular leaks following surgical valve
replacement, and we're specifically discussing the role of
percutaneous device closure exploring the first multi-national
experience form the United Kingdom and Ireland and I'm here with
first author, corresponding author as well, Dr. Patrick Calvert
from Papworth Hospital in the United Kingdom. Welcome Patrick.


 
Dr. Calvert:
It's a great pleasure to be here, thank you for inviting me.


 
Dr. Lam:
Joining us also is Dr. Dharam Kumbhani, associate editor from UT
Southwestern, hi.


 
Dr. Kumbhani:
Hi Carolyn, thanks for having me.


 
Dr. Lam:
Let's get straight into this. It's a problem we've created. How
common is it? Why should we care about talking about perivalvular
leaks?


 
Dr. Calvert:
You know Carolyn, this is actually quite a common problem. The
series we know from previous publications around 5-17% of
surgical valves develop leaks. We know in the early experience of
TAVR that there was quite a problem with leak, although more
recent iterations that's less of a problem. There's a lot of
patients out there that have this problem. It's a difficult
problem to treat because these are, by definition, high-risk
patients and re-operation is not such an inviting thought for
them to have. This is something that needs may be a different
solution than re-operation.


 
Dr. Lam:
Could you tell us what makes your series special?


 
Dr. Calvert:
Yes, so let's talk about the other series first of all. We had a
fabulous series published in 2001 from the Mayo Clinic. That was
a single center of excellence where they are really great at
doing the procedure, but they gave us great insight of a master
class, really if you like, if I had to do the procedure. What is
different about our paper is that it's like a real-world
experience. It's all the centers that contributed in the United
Kingdom and Ireland. It's 20 centers over an 11 year period, in
total 308 procedures. It's, if you like, a warts-and-all approach
to it. It think that's one way it's a little different.


 
 
I think another way that it definitely stands out is that we are
fortunate enough in Europe to have licensed or CE-mark, a number
of oblong devices that are a little different in shape. What we
do know about these holes is, they tend to be crescentic in shape
or at least longer then they are wide. The problem is, if you try
to put a circular device in an oblong hole, it's not going to
work.


 
Dr. Lam:
Which types of perivalvular leak are you talking about here?


 
Dr. Calvert:
We have approximately 50/50 split between the aortic surgical
valve and the micro-surgical valve. Then, about 5% were TAVIs or
TAVRs. Then we had a small number of pulmonic valves and one or
two around angioplastic rings, so that's the proportions. We had
about 57% mechanical valves and 37% bio-prosthetic valves.


 
Dr. Lam:
Wow, first congratulations. That is really important information.
I can already imagine. I see those patients too. Dharam, as an
interventional cardiologist. What is your take on it. Especially
this mention of the oblong devices? They are not FDA approved, so
they won't be in the United States, but what did you think of
that, managing this paper?


 
Dr. Kumbhani:
I think this is a very tricky subset of patients to treat. As
Patrick and his group have shown, that the rates of success can
be very high. As you point out, we don't have all the devices
that they have in the U.S. A lot of us who do this use more
circular devices but they're flexible. The feeling is that they
tend to fit in with whatever geometry of the leak is. I do think
it would be interesting, and probably more appropriate to have
devices that are shaped like these holes are. As Patrick
mentioned, they're usually crescentic, or certainly not round.


 
Dr. Lam:
As a non-interventional cardiologist, I didn't realize it was
very intricate. Tell us about your main findings.


 
Dr. Calvert:
Our principle findings, and what I think is the most important
thing is that, if you're going to do this procedure, you have to
achieve a leak at the end of the procedure, or at least in the
months that follow-up, that is mild or less. In our series, we
showed that those patients that had that, they were independently
associated with less deaths and less major adverse cardiovascular
events. It's a very clear dichotomy between those groups.


 
 
Of course there's all sorts of reasons why you might be able to
achieve a good result in a patient, but we know that if you can
do it, those patients will be very much better than the others.
In our paper we achieved that in around 75% of patients and they
did much better than the others. That is a principle finding.
There were another of other factors that were associated
independently with death and those also included NYHA
classification at follow up, but also creatinine baseline. As
I've already eluded to, this is a high-risk chord of patients and
there are conventional risk factors that will pre-dispose whether
someone's going to do well or not. That's what came out in the
multi-variable analysis.


 
Dr. Lam:
Very important clinically. Take home message from your point?


 
Dr. Kumbhani:
I think one of the interesting findings was that only 16% of
these PVLs were closed for hemolysis. The vast majority of them
were done for symptomatic causes. That probably speaks to the
dictum that it's the smaller PVLs that cause hemolysis. I don't
know if you have a handle, based on your experience, on that?


 
Dr. Calvert:
When we designed the series, a number of years ago ... When you
design a registry you look at the things you're going to collect.
Then when you've written the paper you think, "I just wish I had
collected some more data." That's one of those things we really
wish we looked ... It's fascinating. We do this procedure
together and one of the things we're terrified about is taking a
big leak, getting rid of heart failure and creating hemolysis.


 
Dr. Kumbhani:
Exactly.


 
Dr. Calvert:
We all have had personal experiences of that happening.


 
Dr. Kumbhani:
Yes.


 
Dr. Calvert:
The data we collected, collected patients who had new hemolysis,
requiring transfusion. Therefore, all I can tell you from our
series is, that was really quite a small ... It was only 2 or 3%
of people who had new hemolysis.


 
Dr. Kumbhani:
After the closure?


 
Dr. Calvert:
After the closure. Of course, about 16 or 17% had hemolysis going
into it. It doesn't really tell us any information about what
happened to those, unfortunately.


 
Dr. Kumbhani:
One other interesting thing that I wanted to point out. If you
look at the PCIs registry, all of, there are about 120 hospitals
in it. Is that correct?


 
Dr. Calvert:
That's approximately correct, yes.


 
Dr. Kumbhani:
You had 20 centers that were doing this?


 
Dr. Calvert:
Yes.


 
Dr. Kumbhani:
1 in 6 is doing these in a competent fashion, the PVL closures. I
think, as you pointed out, the series are usually single
institutions that really specialize in this in the U. S. I think
the experience may be a little more consolidated. If you want to
just comment on that finding alone?


 
 
The second thing is, is there something different about the
intervention training procedure in the U.K. that allows for more
interventionists to be comfortable doing this?


 
Dr. Calvert:
I think that's a really great question. I think there's a little
to pick apart behind that. I think the first thing to say is
that, although there were 20 centers that contributed cases, some
of those centers would have definitely had proctors come in to do
the cases. This is the entire learning curve. This is every case
that has contributed in the U.K. It's watching our learning curve
and the lot. There will be a number of centers that have been
heavily proctored coming in.


 
 
One thing that's really nice about the U.K., it's a small
country. Particularly in this structural community, most people
know each other. If you've got a problem, you ring up your friend
down the road and say, "You've done a few of these, come and give
us a hand." We get that and I do that too, so that's great.


 
 
I think the second thing to say, and I think it's important to
say this, our cousins in America are fantastic at doing this
procedure. I think they have to be because although the devices
are malleable, and they will squash because as we both know, it
doesn't matter what the device looks like at the end provided it
plugs the hole and is not interfering with the leaflets and it's
not falling out. That's fine. I do believe that the oblong
devices are more likely to get a good closure. I think therefore,
you're less likely to be having to put in 2 or 3 devices in the
same sitting. I think that's technically demanding for ... I
think it probably is a little more straight forward with the
oblong devices.


 
 
I think it is important to say for the record, that there's
nothing in this paper that is scientifically proven the oblong
devices are better. They trend in their right but, it is a fact
of the series of oblong devices. Once they're available, it was
72% and for the total it's about 2/3. It's not a scientific
comparison but, we've got these good results with these devices.


 
Dr. Kumbhani:
It would not be a fair comparison but in your database, are you
able to do some kind of propensity analysis looking at the oblong
versus the other devices? Comparing ventricle leak for example or
hemolysis?


 
Dr. Calvert:
We don't have enough breakdown data on hemolysis unfortunately. I
think I just need to be careful what I say because a lot of the
authors came up with hypotheses about things. I looked at the
data and I think when we subgroup too much, it became too small
to read to give any careful answers.


 
Dr. Kumbhani:
I see.


 
Dr. Calvert:
I think what would be really fascinating, is when we pool data
with other countries because I know there are other countries
that are looking at this as well. We might get more information,
but that's something we have on the horizon so what this space.


 
Dr. Kumbhani:
That's good.


 
Dr. Lam:
That is fantastic. Thank you Patrick. Thank you Darrin.
Seriously, I'm floored. I learned so much from this and I really
enjoyed this conversation.


 
 
Thank you very much, and to the listeners out there, don't forget
you've been listening to Circulation on the Run. Join us next
week for more highlights and features.