Circulation December 10, 2019 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.


Dr Greg Hundley: And this is Dr Greg Hundley from VCU health, the
Poly Heart Center in Richmond, Virginia. Well, Carolyn, this
week's feature analyzed a pool cohort of all patients in partner
one and partner two, both the trials and registries. Patients had
severe aortic stenosis and were treated with TAVR or SAVR and
then were analyzed with respect to the development of prosthetic
valve endocarditis. But more to come on that later.


Dr Carolyn Lam: Let me start by telling you about my picks from
this week's journal. So the first one is a really interesting
natural experiment. First, do you think that a short term visit
to a location with severe air pollution increases the risk of
cardiovascular disease?


Dr Greg Hundley: Well, Carolyn, I would say yes.


Dr Carolyn Lam: Greg, you're too smart. But let me tell you what
these investigators did. So their co-corresponding authors, Dr
Araujo from David Geffen School of Medicine and UCLA, Dr Zhu from
UCLA Fielding School of Public Health, and Dr Qiu from College of
Environmental Sciences and Engineering in Peking University.
These co-corresponding authors and their colleagues did a natural
experiment by collecting urine and blood samples from 26 healthy
adult residents of Los Angeles before, during, and after they
spent 10 weeks in Beijing during the summer of 2014 and 2015.


Dr Greg Hundley: I am really excited to hear this. Carolyn, what
did they find?


Dr Carolyn Lam: So traveling from less polluted Los Angeles to
more polluted Beijing induced pro oxidative and pro inflammatory
effects, which reversed after returning to Los Angeles. This is
also the first human study associating exposures to polycyclic
aromatic hydrocarbons with changes in paraoxonase 1, enzymatic
activity, and circulating levels of hydroxyeicosatetraenoic and
hydroxyoctadecadienoic acids. Cool, huh?


Dr Greg Hundley: Absolutely. Carolyn, you did an awesome job.
Very nice. Well, my article comes from the world of basic science
and it's from Dr Philip Shaul at the University of Texas
Southwestern medical Center. So Carolyn, in recent studies of
obesity induced insulin resistance in mice with corroborating
findings in human type 2 diabetics, this group, Shaul’s group,
previously made the surprising discovery that the insulin
resistance is driven by an altered post-translational
modification in IgG that leads to enhanced activation of FCYR2B
in endothelial cells. And as a result, there is an attenuation of
insulin transcytosis across endothelial cells and delivery to
skeletal muscle myocytes where up to 80% of glucose disposal
usually occurs.


Dr Carolyn Lam: Oh. Interesting, Greg. So what did the authors
find in the study and how did these findings equate with obesity
and hypertension?


Dr Greg Hundley: Well, they found that hyposialyation of the Fc
glycan on IgG is identified as a key contributing factor in
obesity induced hypertension. And therefore low levels of IgG Fc
glycan sialylation may identify individuals at greater risk of
developing hypertension. In addition, the degree of sialylation
of IgG may predict the relative response of an individual to any
hypertensive therapy.


Dr Carolyn Lam: Nice. So my next paper is from Dr Al-Lamee from
Imperial College, London, and colleagues who studied the ability
of a pre-randomization stress echocardiographic score to predict
the placebo-controlled efficacy of PCI within the ORBITA trial.
Now as a reminder, the primary results of the ORBITA trial showed
us smaller than expected effect size of PCI in comparison with
placebo in single vessel stable coronary artery disease on the
primary end point of change in treadmill exercise time.


Now in the current study, 183 patients underwent dobutamine
stress echo cardiography before randomization, and they found
that the degree of ischemia assessed by dobutamine stress echo
cardiography predicted the placebo-controlled efficacy of PCI on
patient reported angina frequency.


Dr Greg Hundley: Hmm. Very interesting. So help me out again,
Carolyn. What's the clinical importance of this?


Dr Carolyn Lam: Ah, so this study really provides the first
placebo-controlled evidence of an association between stress echo
cardiography, ischemia, and the magnitude of placebo-controlled
benefit attributable to PCI. And the greater the downstream
stress echo cardiography abnormality caused by the stenosis, the
greater the reduction in symptoms from PCI. That's the take home.


Dr Greg Hundley: Oh wow. Very interesting. You know, especially
we perform so many stress echo cardiograms. What a great
relationship to unfold and present. Well, Carolyn, I'm going to
walk through several other important publications in this issue
of the journal. The first is from Dr Peter Eckman from the
Minneapolis Heart Institute, and he provides an In-Depth review
of veno-arterial extra corporal membrane oxygenation, or VA-ECMO,
for cardiogenic shock and it's beautifully written for the busy
clinician. Robert Platt, PhD, and colleagues discuss in an On My
Mind piece the fact that those with adverse cardiovascular
sequelae during pregnancy may require development of new
cardiovascular risk prediction models. The hypertension or the
diabetes that occurs during pregnancy, perhaps we need to
incorporate that into our prediction models.


Next. Our own associate editor Torbjørn Omland provides results
in a research letter from the peace trial relating the
relationship between smoking and high sensitivity troponin T
levels. Dr Allen Sniderman from McGill University Health Center
writes a letter to Welsh and Associates regarding their study of
the UK bio bank database and measures of HDLC. A paper we
discussed just a few weeks ago. Dr Derek Chew from the DCRI and
Durham North Carolina has another EKG challenge for us. And Dr
Tracy Hampton provides an updated news report regarding
cardiovascular disease from several recently published articles
in the world of basic science. And then finally Dr Thomas Krieg
from the University of Cambridge has a nice piece regarding
clinical implications of targeting succinate metabolism in
ischemia reperfusion injury.


Well, Carolyn, what a great slate, but I can't wait to get to
that feature discussion related to prosthetic valve endocarditis.


Dr Carolyn Lam: Me too. Let's go.


Our feature discussion today is really the first paper that
describes adjudicated evaluation of prosthetic valve endocarditis
in patients with transcatheter and surgical aortic valve
replacement. Very unique and valuable data from the partner's
trial. I'm so pleased to have with us the corresponding author,
Dr Wael Jaber from Cleveland Clinic as well as our associate
editor, Dr Manos Brilakis from UT Southwestern. So Wael, very
unique question. Could you please tell us how you went about
doing this? And I suppose in this setting, the first question on
everyone's mind is how did you make this diagnosis of prosthetic
valve endocarditis?


Dr Wael Jaber: Actually we saw this as an opportunity that
probably we should never miss. I think this is one of the rarer
instances where we can objectively not only look at SAVR data but
also TAVR data. And over the past maybe seven years, eight years,
we started getting here as a referral center patients with TAVR
endocarditis for surgery. And we never thought we'd start seeing
these weird organisms, different bugs. Of course this is a
population that's frail or elderly, but we never had any idea if
they behave similarly to SAVR or differently than SAVR in our
previous experience with SAVR endocarditis.


So we planned this actually about maybe five years ago, but we
didn't have the data because you know the partner trials were
undergoing another evolution by going to lower and lower risk
population. So we pose this question about a year and a half ago
to CRS by asking them, can you provide us with the data on all
the endocarditis in partner.


The idea was not only to answer one question but to answer
multiple questions. So the first question was in the modern era,
what happens in SAVR? All the SAVR endocarditis information we
have so far as you will know has been from mainly single center
studies or even when we learn about it from multiple centers
sites, usually IN European studies, the Swedish registry, the
Danish registry, and these are usually limited by the fact that
there are a multicenter. The adjudication is at the site what
endocarditis happened. So that was the first question. Then the
second issue for us was, does TAVR, because of the unusual access
to the heart and the fact that we dilate the valve, post dilate
the valve, their paravalvular AI, they could be micro-fractures
of the refis. This is provide a different opportunity for these
bugs to form on the valve, and do they behave differently?


And the third question was, is there any difference between SAVR
and TAVR incidence of endocarditis? And bugs. And the final
question was what happens to patients when they develop
endocarditis in the current decade. Do they do well? Especially
for septic endocarditis or do they succumb to their illness? And
also this is how we came up with a strategy to answer all these
questions.


Dr Carolyn Lam: Very nice. So Wael, could you just expand a
little bit more about how the diagnosis or adjudication of
prosthetic valve endocarditis was done? And then tell us please,
what did you find?


Dr Wael Jaber: All the partner patients, the records were sent to
a central place. So the ECHOS first were educated at central
places. We were one of those centers. Other places were Columbia
University, MedStar and Quebec, the group in Quebec. So all the
ECHOS were adjudicated centrally. So that's first, as far as from
the echo side of calling it endocarditis or not.


On the clinical side, again, all the records and the forms were
sent to a central adjudication committee, CDC group. We served at
the Cleveland Clinic as the CDC for most of these trials and
actually even for the current trials. So they were sent and they
were adjudicated according to the Duke criteria. Which is, you
know, the most, probably, reliable way still today to adjudicate
these.


And then there was the CDC and the echo core labs were separate.
So the people who have information from the CDC did not have
access to what's going on in the core lab and vice versa. So
these were independently adjudicated as far as echocardiographic
evidence and clinical evidence. And then they were fed into it.
So by the end, when you hold it on a Duke criteria endocarditis,
the echo was fed after the fact, not before. So this is in
general how it happened. So all the events were educated
centrally, not at the site. And the ECHOS, the same thing, were
adjudicated centrally.


Dr Carolyn Lam: Fantastic. And I would love to hear the results.


Dr Wael Jaber: The first question was, what's the incidence of
endocarditis? And we decided because of the way these trials were
done, to report the incidents as you would see in the results
section, to report the incidents of endocarditis per 1000 person
year because of the imbalances in follow up and the competing
risk for death from other reasons. So we found in general that
the incidents of endocarditis was 5.2 endocarditis events per
1000 patients per year in the TAVR side and 4.1 in the SAVR side
with a non statistically significant difference. More
importantly, we found out that once you develop endocarditis,
unfortunately most of these patients succumb to the illness and
are dead after the diagnosis. So the risk of dying after
developing endocarditis is 4.4 times higher than patients who did
not have endocarditis in the trials. In all the trials.


Now there's some caveats here. First, these are trials with
different patient populations, as you well know. Starting with
partner with the inoperable patients moving on to the most modern
S3 trial, which was on the lowest kind of side of population. So
we have totally different population groups. Some of them had
prolonged hospitalizations before and after, so this should be
taken with a little bit of caution.


However, if you look at some of the individual trial data, we
found that incidents of endocarditis at least have a trend
towards a reduction of incidence of endocarditis over time going
from partner, the initial experience with partner, all the way to
the modern era.


Dr Carolyn Lam: That is so great. Manos, you know, as an
interventional cardiologist yourself, could you tell us how
important these results are? Does it affect your practice?


Dr Emmanouil Brilakis: Thanks again, Carolyn. I would like to
congratulate Wael for a phenomenal paper. I think it's a very
timely study and addresses one of the common concerns there is
about whether TAVR does predispose people to more risk for
endocarditis. Although again, the opposite grade was kind of low
at 0.5% a year. I think this may be a little more than people are
commonly seeing in the setting of TAVR, and I think the paper is
a good reminder that this is something we should always be
mindful and watching. Although typically we'll discuss with the
patient about the risk of stroke or access complications, but the
risk of infection may not be as well emphasized. And based on
this one question I would have is about what can we do if there
is something that could potentially lower that risk? I understand
the limitations of retrospective study, but are there any
recommendations that you have based on the study? Should give
more aggressive antimicrobial therapy? Any other biotic
prophylaxis or anything else that can be done to reduce the risk
of endocarditis in those patients?


Dr Wael Jaber: Actually this is the question we raised.
Unfortunately we did not. So the guidelines did not catch up with
what we know. So if you look right now, like I was reviewing this
paper that came up last month from the Swedish Registry for
Endocarditis, it came out in Europe in the European Heart
Journal, and one of the questions they raised is how to address,
in the editorial, how to address the risk of endocarditis and
prophylaxis in this population. There are no standards for that.
This is one aspect of it. We need first an update of the
guidelines of how to address this issue.


The second question is we do not have any idea, unfortunately,
about duration of antibiotics. How the antibiotics prophylaxis
were given before the procedure, like as we do right now commonly
in surgery, and after the procedure in these patients. We do not
know that. Like right now, at least at our center, if you go in
for aortic or mitral valve surgery or any valve surgery, you have
to have a dental clearance before you start, before you go to
surgery. I don't know if this was rigorously applied in the
setting of TAVR, and I think it would be a good idea to apply it
to make sure that there are no dental, phosphide or potential
infections and things like that. So I think it's a multi-front
battle to get these patients to the lowest risk possible. I don't
think there's one single silver bullet here.


Dr Emmanouil Brilakis: So thanks again, Wael for addressing this.
I agree that there's a lot of information to be gained
understanding the intricacies of endocarditis prophylaxis. And
building on this, let's say another patient develops endocarditis
as you've shown in your 170 patients in the study. It was
fascinating that staph aureus was actually less common than it
was for surgical valves, which has been shown in other studies as
well. So you think this affects the choice of the biotic
prophylaxis? And then also if the patient develops endocarditis,
I understand many people who are not candidates for surgery, but
from the ones who did actually undergo surgery, what are the
outcomes encouraging?


Dr Wael Jaber: This is a fascinating question actually. This is
one of the reasons we had... There was a delay for us in getting
the paper out from when we presented it as an abstract at TCT a
year and a half ago, is we didn't know. We wanted to answer that
question. The second part of the question is how many patients
went to surgery? And unfortunately, very few patients. So less
than a handful of patients end up going to surgery. And we do not
know why. So this is the dilemma here. Is why the rate of
referral to surgery for redo surgery was very low.


Was it because these patients were the sickest of the sick? Maybe
it is because we waited too long and we did not treat them the
same way. We should have treated prosthetic valve endocarditis,
which is surgery to be offered as soon as possible because
there's no really antibiotic cure for that. So we do not have the
answer for that because these very few patients went to surgery
and actually I think of those who went to surgery, even the
mortality there even was similar to people who did not go to
surgery. But we cannot speculate on that because the very few
patients.


As far as the bug involved, I think this could be a reflection of
the antibiotics given at the time of the procedure, so probably
we're covering that very well. But if you notice from the paper,
most of the infections happen more than 30 days after the
procedure. Whether this is something that was acquired because
these patients are more likely to end up in the hospital again
for other reasons, whether these patients had endocarditis
because they have more instrumentation down the road... Remember
this is a population in general above the age of 65 which would
require colonoscopies, frequent urinary tract issues, and other
procedures.


So we know that we're covering very well, at least I can
speculate, we're covering very well for the first 30 days because
very few patients had endocarditis right after the procedure, but
we're not covering probably after the 30 days. And that remains
to be studied. And the worrisome thing is to try to treat these
patients with prophylactic antibiotics for a long time and then
end up with bug resistance and things like that. Now the CDC
issued a big warning about this yesterday. I am not comfortable
to speculate from this small number of patients on how to treat
for prophylaxis, but I'm comfortable to say probably patients
should be sent to surgery as soon as possible after developing
endocarditis, especially prosthetic valve endocarditis because
the outcomes are dismal.


Dr Emmanouil Brilakis: And do you think... Let's say patient is
not a candidate for surgery and gets endocarditis, and I presume
they get into prolonged therapy. There were some patients like
this that did okay, right? So there is some hope even for those
patients.


Dr Wael Jaber: I feel like I'm the cup half full here because if
you look at the mortality curves here, we're talking about north
of 95% death in this population. So the people who survive this
must be very few people survive. So probably about seven patients
who survive. So the mortality was 96% at six months versus 46%.
So there are very few people who survived that event. Maybe I
should go back now and figure out what was the quality of life
after survival. So I don't think the picture we have right now is
very rosy as far as the way we're managing endocarditis.


Dr Carolyn Lam: Manos, I'm going to give you the final parting
words from this very interesting discussion. I mean what do you
think are the take home messages and future directions from here?


Dr Emmanouil Brilakis: I agree that this is a phenomenal landmark
study and my key takeaways are the same ones that Dr Jaber
presented before. But the main thing is, on the consent process,
who can tell the patients there is about 0.5% per year. So it's
not zero, but it's very high either. The second thing is that
this choice between TAVR versus SAVR, that should not have to do
with the risk of infection because as it was shown very
convincingly, it was very similar to the two groups. And number
three that everything possible should be done to prevent this
because if you do get infection, the outcomes are not very good.


Dr Carolyn Lam: Thank you so much Manos, Wael. Thank you so much
audience for joining us today. You've been listening to
Circulation on the Run. Tune in again next week.


This program is copyright American Heart Association 2019.