Circulation June 6, 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 featured paper today
provides important trial evidence that will guide interventional
management of symptomatic femoral artery disease, but first,
here's your summary of this week's journal.


                                               
The first paper sheds light on the interaction between left
ventricular dysfunction and mesenchymal stromal cell activation.
First author, Dr. Naftali-Shani. Corresponding author, Dr. Leor
and colleagues from Neufeld Cardiac Research Institute in Israel
isolated mesenchymal stromal cells from cardiac and subcutaneous
fat tissues of mice with left ventricular dysfunction, 28 days
after myocardial infarction or sham operation. They further
injected mesenchymal stromal cells or saline into the infracted
myocardium of mice and evaluated left ventricular remodeling 28
days after myocardial infarction. They found that left
ventricular dysfunction switched cardiac mesenchymal stromal
cells towards an inflammatory phenotype and that these
pro-inflammatory mesenchymal stromal cells contributed to adverse
left ventricular remodeling and dysfunction. The inflammatory
polarization of cardiac mesenchymal stromal cells by left
ventricular dysfunction was mediated by toll-like receptor four.
Finally, toll-like receptor four deficiency in mesenchymal
stromal cells attenuated their pro-inflammatory activation,
improved their reparative properties, graft survival, infarct
repair and left ventricular remodeling.


                                               
In summary, the environment of the failing and infarcted
myocardium drove resident and transplanted mesenchymal stromal
cells towards a pro-inflammatory phenotype that restricted their
survival and reparative effects in a mechanism mediated by
toll-like receptor four. Targeting toll-like receptor four in
mesenchymal stromal cells could improve the safety and efficacy
of cell therapy in heart failure.


                                               
The next study provides evidence that fractional flow reserve or
FFR is a useful index for decision-making in real life daily cath
lab practice. First author, Dr. Ahn, corresponding author, Dr.
Park and colleagues from Heart Institute Asan Medical Center in
South Korea, evaluated the prognosis of deferred and
revascularized coronary stenosis after FFR measurement in the
IRIS-FFR registry of 5,848 prospectively enrolled patients. This
large prospective registry showed that the FFR was linearly
associated with the risk of cardiac events in deferred lesions.
In addition, revascularization for coronary artery stenosis with
a low FFR of less than 0.75 was associated with better outcomes
than deferral, while for a stenosis with a high FFR of greater
than 0.76, medical treatment would be a reasonable and safe
strategy. Thus, the authors concluded that FFR may be considered
a clinical prognostic index in addition to a physiological
quantification for flow-limiting stenosis. These and other issues
are discussed in an accompanying editorial by Doctors De Bruyne,
Fournier and Barbato.


                                               
The next study sheds important insights into a potential disease
modifier in pulmonary arterial hypertenstion, and that is
vascular endothelial growth factor receptor three, or VEGF
receptor three. First author, Dr. Hwangbo, Co-corresponding
authors Dr. Chun and Dr. Jin from Yale Cardiovascular Research
Center in Connecticut, used a combination of experimental animal
models, human patient cells and detailed signaling studies to
demonstrate the importance of a novel interaction between bone
morphogenetic protein type two receptors, or BMPR2 and VEGF
receptor three in regulating the robustness of endothelial bone
morphogenic protein signaling response. They demonstrated that
the interaction was critical for promoting BMPR2 internalization
in response to bone morphogenic protein stimulation. They further
showed that genetic deletion of endothelial VEGF receptor three
in mice resulted in exacerbation of chronic hypoxia-induced
pulmonary hypertension and impaired bone morphogenic protein
signaling. Thus, these findings identify VEGF receptor three as a
key regulator of endothelial BMPR2 signaling and a potential
determinant of pulmonary arterial hypertension penetrance in
humans.


                                               
The next study tells us that a low-dose drug-coated balloon may
be a promising treatment option in symptomatic superficial
femoral or popliteal artery disease. Dr. Schroeder and colleagues
of the Jewish Hospital in Berlin, Germany, reported results of
the ILLUMENATE European Randomized Clinical Trial, which was a
prospective randomized multi-center, single-blinded trial, where
patients were randomized 3:1 to treatment with a low-dose
drug-coated balloon or an uncoated percutaneous transluminal
angioplasty balloon. The primary safety endpoint was a composite
of freedom from device and procedure-related death through 30
days, and freedom from target limb major amputation and
clinically-driven target lesion revascularization through 12
months. The primary effectiveness endpoint was primary patency at
12 months. The main results were that in symptomatic patients,
with superficial femoral and/or proximal popliteal artery
disease, low-dose, drug-coated balloon was safer and more
effective than uncoated percutaneous transluminal angioplasty
balloons through follow-up of 12 months. This is discussed as a
novel strategy to reduce femoral popliteal restenosis in an
accompanying editorial by Doctors Goldsweig and Aronow.


                                               
The final study provides important genotype-phenotype
correlations of SCN5A mutations in probands with Brugada
syndrome. First author, Dr. Yamagata, corresponding author, Dr.
Shimizu and colleagues of Nippon Medical School in Tokyo, Japan,
studied 415 Japanese Brugada syndrome probands to assess the
association between SCN5A mutations and clinical outcomes. During
a mean follow-up period of 72 months, the overall cardiac event
rate was 2.5% per year. Compared to probands without mutations,
probands with SCN5A mutations experienced their first cardiac
event at a younger age, had a higher positive rate of late
potentials and exhibited longer P-wave, PQ and QRS durations, and
had a higher rate of cardiac events, especially when the
mutations were located in the pore region of the encoded protein.
The conclusion was therefore, that genetic screening for SCN5A
mutations among Brugada syndrome probands may be useful for
stratifying such patients according to their risk of subsequent
cardiac events. Well, that wraps it up for your summaries. Now
for our feature discussion.


                                               
Our feature paper today is the stuff that really could change
guidelines. Now, we're talking about superficial femoral artery
disease and its treatment. Unlike most other vascular beds, where
stenting is the preferred modality of endovascular
revascularization, the optimal therapy for superficial femoral
artery disease remain controversial. However, today's paper
really adds to our insight and I am so pleased to have the first
and corresponding author Dr. Ilka Ott, from German Heart Center
in Munich, as well as Dr. Manos Brilakis, Associate Editor, from
UT Southwestern. Welcome both.


Dr. Ilka
Ott:                        
Welcome.


Dr. Manos
Brilakis:          
Morning.


Dr. Carolyn
Lam:              
Wonderful. So Ilka could you please share what you found?


Dr. Ilka
Ott:                        
We already know from previous studies there has been a lot of
studies showing the drug-eluting balloon is superior to plain
angioplasty in superficial artery disease. So then, in our study,
we found that the treatment with the drug-eluting balloon plus
stenting was very superior to the balloon angioplasty plus
stenting and the directional atherectomy. The primary endpoint we
used in the study was an angiographic endpoint. It was diameter
of stenosis and this was significantly lower in the patients
treated by drug-eluting balloon angioplasty, as compared to the
balloon angioplasty and atherectomy group. Moreover, we had a
clinical follow-up of 24 months and we found that also the target
lesion revascularization was 70% in the group of drug-eluting
balloon plus stent as compared to 37% in the balloon angioplasty
and stent group, and 53% in the atherectomy group. We found a
significant reduction also in the clinical endpoint of TLR at
three years.


Dr. Carolyn
Lam:              
Wow Ilka, congratulations, but may I just ask, was there any
reason to think that a drug-eluting balloon would not be
similarly beneficial as in other vascular beds?


Dr. Ilka
Ott:                        
Well, I think is not a novelty of the study. We already know from
previous studies that drug-eluting balloon is superior to plain
balloon angioplasty so that's not a surprising result. However,
in disease of the femoral superficial artery we often have the
problems, in particular when we treat complex lesions like along
occlusions or along calcified stenosis, that drug-eluting balloon
is not sufficient, so you need to also stabilize the lesion to
stabilize dissections. You also need to do a stent implantation.
Our study now shows that the combination of drug-eluting balloon
plus stent is superior than plain balloon angioplasty plus stent.
The nice approach is most of the time if you need a stent, if you
use drug-eluting balloon and the lesion is stable and you don't
need a stent you are glad. This has shown previous studies,
however, if you need further treatment and you need to place a
stent, we now show that the pretreatment with a drug-eluting
balloon is a superior option than just the plain balloon
angioplasty.


Dr. Carolyn
Lam:              
Manos, what is your take on these results? Do you think it will
impact guidelines?


Dr. Manos
Brilakis:          
First of all, I would like to congratulate Dr. Ott for an
excellent study. I think what is particularly important here, is
the comparative effectiveness component. We have several studies
circulating already about drug-coated balloons, have studies on
stents, but we don't have studies addressing the other modalities
like atherectomy. Why I was particularly impressed, is I think
the study will have a finally an assessment of atherectomy as a
primary strategy for calcified lesions and it's interesting that
that was not as good efficacy. It was actually tents for worse
TLR as compared to plain old balloon angioplasty and stent. Would
like to ask Dr. Ott what is your kind thoughts about the alone
atherectomy give the results of the study? Are they still doing
it or is it falling out of favor?


Dr. Ilka
Ott:                        
Yes, I think this is a very important point. I think atherectomy
alone is not an appropriate treatment but there are some data
that atherectomy in combination with drug-eluting balloon gives
much better results, or you may even think about a combination of
atherectomy and drug-eluting stent, so it often is the case. This
study also raises a lot of questions and gives some thought into
further studies. I think in the combination atherectomy might
still have its place.


Dr. Carolyn
Lam:              
Could you tell us some of those plans for future studies?


Dr. Ilka
Ott:                        
Well, we are just in the initiation phase but I think one also
very interesting concept is to compare drug-eluting balloon plus
stent to the drug-eluting stents that have been on the market.
However, as I said before, there's again the concept if you
combine the drug-eluting balloon plus a stent it might be also,
from the commercial aspect, better because sometimes you don't
need the stent. And then moreover, the drug-eluting stents are
much more expensive. It would be interested to see a study like
that.


Dr. Carolyn
Lam:              
What about the concern that the superficial femoral artery is
subject to a lot of stretching and external compression and it's
long and ... Maybe I'm out of date here about the concern of
stent fractures and so on. It looks like your study has disproven
this, or do you think the follow-up's long enough?


Dr. Ilka
Ott:                        
I think the follow-up of two years is quite good, but you're
right, it seems like in the superficial femoral artery the
restenosis process is much longer and more prolonged. Of course,
you would like not to place a stent in the SSA but from the
interventional aspect, it's often not possible because if you
have a dissection with a limiting the flow, you have to fix that
by putting in a stent. Nitinol stents are pretty good these days.
Moreover, we have another generation of the woven stents the
Supera stents that might also be an interesting point to
investigate in comparison to the strategy we now have shown to be
superior.


Dr. Manos
Brilakis:          
I think what we need is more studies like this, that they take
the other modalities like atherectomy, laser and combine them
with what is currently the standard of care, which is drug-coated
balloons or drug-coated balloons plus stent, as shared in the
study. I just want to congratulate Dr. Ott on her study and
encourage future studies from the group. I know the ISAR group is
been a phenomenally productive group in coronary intervention and
I'm delighted to see they're expanding on the peripheral world.


Dr. Carolyn
Lam:              
I couldn't agree more. Congratulations, once again, for a study
that really will impact practice and that we're so proud to be
publishing in Circulation.


                                               
Listeners, I'm sure you learned as much as me, so please don't
forget to tune in next week as well. Thanks.