Circulation September 5, 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. Today's feature paper
looks at the early use of N-Acetyl Cysteine with nitrate therapy
in patients undergoing primary PCI for STEMI. More soon right
after this week's summary of original articles.


                                               
The first paper identifies a novel association between
Phosphatidyl Choline Transfer Protein, or PCTP expression, in the
blood, and death or myocardial infarction in patients with
cardiovascular disease. Now, PCTP regulates intermembrane
transfer for phosphatidyl choline. Platelet PCTP expression has
been shown to be associated with increased platelet responses
upon activation of protease-activated receptor four thrombin
receptors. In today's paper, first authors Dr. Mao and Songdej,
corresponding author Doctor Rao, and colleagues from the Temple
University School of Medicine in Philadelphia used DNA protein
binding studies and human erythroleukemia cells, as well as
luciferase reporter studies to show that PCTP is a direct
transcriptional target of RUNX1, a major hematopoietic
transcription factor that regulates platelet production and
function. Furthermore, in 587 patients with cardiovascular
disease, the authors showed that PCTP expression in the blood
correlated with RUNX1 expression and was independently associated
with future death or myocardial infarction. Thus, regulation of
PCTP by transcription factor RUNX1 may play a role in the
pathogenesis of platelet-mediated cardiovascular events.


                                               
The next paper provides molecular insights into cardiac fibrosis
and shows that bone marrow cells are involved in cardiac fibrosis
during pathological stress. Drs. Kishore, Verma and colleagues
from Lewis Katz School of Medicine and Temple University of
Philadelphia hypothesize that interleukin-10 inhibits pressure
overload-induced homing of bone marrow fibroblast progenitor
cells to the heart, and inhibits their trans-differentiation to
myofibroblasts, thus attenuating cardiac fibrosis. To test this
hypothesis, the authors used pressure-overload in wild-type and
interleukin-10 knockout mice by transverse aortic constriction,
and used chimeric mice to determine bone marrow origin. They
further isolated fibroblast progenitor cells from mouse bone
marrow for mechanistic studies.


                                               
They found that, in addition to resident cardiac fibroblasts,
bone marrow-derived fibroblasts significantly contributed to
progression of pathological cardiac fibrosis, and that pliotropic
antiinflammatory interleukin-10 inhibited the recruitment and
trans-differentiation of bone marrow fibroblast progenitor cells
in the pressure-overloaded myocardium. At a molecular level, they
showed that interleukin-10 inhibited TGFβ SMAD2-3 signaling in
activated bone marrow fibroblast progenitor cells. Furthermore,
inhibition of TGFβ SMAD2-3 signaling mediated micro-RNA21
maturation was a novel mechanism by which interleukin-10
inhibited bone marrow progenitor cells-mediated cardiac fibrosis.
Thus, selective inhibition of bone marrow cells homing to the
heart and of fibrotic signaling using interleukin-10 or selective
RNAs might inhibit the transition of physiological hypertrophy to
heart failure, and may be a potential therapeutic target to treat
or prevent the development of hypertrophic remodeling.


                                               
The next study looks at the risk of major bleeding in patients
receiving ticagrelor compared to Aspirin after a TIA or Acute
Ischemic Stroke in the SOCRATES study. As a reminder, the
SOCRATES trial was the first outcome study with ticagrelor in
patients with Acute Ischemic Stroke or TIA, who were given ninety
days of monotherapy with ticagrelor, 90 milligrams, twice daily
and compared with those given aspirin 100 milligrams daily. The
trial found that ticagrelor was not superior to aspirin in
reducing the primary composite endpoint of stroke myocardial
infarction or death. In today's study, Dr. Easton and colleagues
from University of California San Francisco aimed to describe the
bleeding profile of monotherapy with ticagrelor versus aspirin in
this population of patients with Acute Ischemic Stroke and TIA,
to characterize major bleeding based on the PLATO, TIMI and GUSTO
bleeding definitions, and to identify factors associated with
major bleeding.


                                               
They found that PLATO major bleeds occurred in 0.5% of patients
on ticagrelor and 0.6% of patients on aspirin. The most common
locations of major bleeds were intracranial and gastrointestinal.
Intracranial hemorrhage was reported in 12 patients, or 0.2%, on
ticagrelor and 18 patients, or 0.3%, in aspirin. Independent of
bleeding classification, PLATO, TIMI or GUSTO, the relative
difference between treatments for major or severe bleedings was
similar. However, non-major bleeds were more common on
ticagrelor. Thus, this paper contributes important data on the
bleeding profile of ticagrelor in patients with acute cerebral
ischemia, provides some reassurance that there's no increased
risk of major bleedings with ticagrelor compared to aspirin,
including intracranial bleeds, however, a numerical increase in
minor bleedings with ticagrelor.


                                               
The next paper tells us that single 24-hour urine collections may
be useful for estimation of average sodium intake in populations.
However, for a reliable estimation of cardiovascular and renal
risk, multiple 24-hour urine collections may be needed. First
author, Dr. Olde Engberink, corresponding author, Dr. Vogt and
colleagues from Academic Medical Center Amsterdam selected 574
adults with EGFR above 60, an outpatient 24-hour urine sample,
and at least one collection during a seventeen year follow-up.
Sodium intake was estimated using a single baseline collection,
and the average of samples that were collected during a one,
five, and fifteen year follow-up.


                                               
They found that estimates of daily sodium intake changed more
than 0.8 grams in half of the subjects when using multiple
follow-up collections instead of a single baseline collection.
The way of estimating sodium intake significantly affected the
observed relationship between sodium intake and long-term
outcome. Hazard ratios for cardiovascular and renal outcomes
changed up to 85% when multiple follow-up 24-hour urine
collections were used, instead of a single baseline collection.
Thus, in summary, relative to a single baseline, the use of
subsequent 24-hour urine samples resulted in different
estimations of an individual's sodium intake, while population
averages remained similar. This had significant consequences for
the association between sodium intake and long-term
cardiovascular and renal outcome.


                                               
That wraps it up for your summaries this week. Now to our
featured discussion.


                                               
Today for our featured discussion, we are talking about
approaches to cardio protection. Now, we all know that the
mortality rates in STEMI has improved over the last few years,
because we've gotten better at reperfusion therapy with primary
PCI, as well as effective secondary prevention therapy. However,
the incidents and severity of heart failure following STEMI has
been rising and thus, cario-protective therapies are of great
interest to prevent heart failure and improve overall clinical
outcomes following STEMI, following primary PCI. Over the years,
a number of cardio-protective therapies have been tried, but have
either been unable to reduce MI size or improve clinical outcomes
following STEMI, but in this week's journal, we have an exciting
trial, very interestingly of two old cardio-protective therapies
showing a lot of promise in this area. And to do discuss this, I
am so pleased to have the corresponding author, Dr. John Beltrame
from University of Adelaide in Australia, as well as associate
editor from Brigham and Women's Hospital in Boston,
Massachusetts, Dr. Laura Mauri.


                                               
John, you know, in my introduction I said this is very
interesting. You're actually combining two old therapies,
N-acetylcysteine and nitroglycerin in your approach in this
trial. Now, both these drugs have been around for a long time.
Please share with us what led you to think that a combination
would work, what made you test the combination, and what makes
your trial different from the other reperfusion studies before.


Dr. John
Beltrame:          
So, nitroglycerin, of course, has been utilized to treat
myocardial infarctions for many years, has been shown to reduce
the chest pain in that scenario, but little reward in perhaps
reducing infarct size. And one of the main benefits of that
people don't know is the vasodilation effect that it has on the
coronary arteries, as well as reducing the wall stress. So, what
we thought to combine it with N-acetylcysteine, which potentiates
nitroglycerin effects, but also is a free radical scavenger. So
therefore it would actually also work on reperfusion injuries. So
these have a very synergistic effect, and therefore we expected
to have good benefits.


                                               
The ... because we're also looking at an anti-ischemic therapy
with a reperfusion protective therapy, we wanted to introduce it
as soon as possible. And so this drug was initiated in the
emergency department as patients arrived, and then taken off to
the cath lab where it was continued. We also began to ensure that
we had adequate N-acetylcysteine, which I'll probably refer to as
NHC from now on, as much on board as possible before we actually
opened the artery. We gave high dose N-acetylcysteine at 20
milligrams in the first thirty minutes, and then at a slower rate
for the next twenty-four hours. So for the first hour we gave it
at 20 milligrams a minute, and then thereafter 10 milligrams a
minute. And then, the actual study. We had patients randomized
and double-blind placebo control trial, multiple sites here
within South Australia with the primary endpoint being myocardial
infarct size on early cardiac MRIs.


                                               
So they got to see the opportunity to have a smaller sample size
than many of the conventional infarct studies, and the key
finding was in that early MRI, we saw an absolute 5% reduction in
infarct size, which was an exciting find for us and this we
expect to translate to a significant reduction in cardiovascular
events and that's where I guess we're going in the future, is
that we need to now undertake a study where we show that the
combination of these two drugs also impacts on cardiac events.


Dr. Carolyn
Lam:              
How beautifully summarized, John. And really, congratulations on
such an impactful and elegantly done study. I like the way you
highlight it, though. Basically, you gave this drug earlier than
most other trials of reperfusion therapies, because you gave it
even before the primary PCI procedure as most cardio-protective
strategies were tried within the cath lab. Would that be
accurate?


Dr. John
Beltrame:          
Exactly right. So, whereas a number of the studies would take the
patient with the STEMI to the cath lab, undertake the diagnostic
angiogram and the diagnostic angiogram would then confirm that
this was occluded, then they would introduce the
cardio-protective agent and then proceed on to open up the
artery. Whereas we had an opportunity for sort of ... at least
twenty to thirty minutes before the artery was opened to actually
have those drugs on board. And so, in a number of cases, we
improved the patency of the vessel when we got to the diagnostic
angiogram. So it's a two-point strategy, one anti-ischemic and
one cardio-protective in terms of reperfusion injury. And we
think that future trials in this area need to address both those
conditions.


Dr. Carolyn
Lam:              
I can think of no better person to comment on being able to do
these trials and the future of these trials than Laura. Laura,
what are your thoughts?


Dr. Laura
Mauri:              
Thanks Carolyn. John, that was a great summary and I think you're
really to be commended, because this is just such a challenging
area to be doing trials in, but that's really what we need. And
you know, most of the trials have focused on early procedure
success for therapies that we currently use, rather than showing
documented benefit in longer-term endpoints. But as you mentioned
earlier, Carolyn, we really do still have patients who would
benefit from therapies that may reduce infarct size. I think it's
really remarkable, John, that your study was able to intervene
early in the emergency room, as we know as clinicians that's not
easy to do, not only to activate the quick pathways of care that
we need for STEMI, but then on top of that to lay on a randomized
trial, but I think it's incredibly important.


                                               
What are you foreseeing as the challenges? As you think about
your next steps in rolling this out to a ... potentially a larger
trial and implementing such a study?


Dr. John
Beltrame:          
As with many trials, it's ways of recruitment, because a study
like this is not gonna be funded by industry, you need to be
looking at ... here within Australia, be looking at government
authorities to put in an application for funding and then, it's a
matter of recruiting. That's one of challenges we came across in
doing this particular study, and this relates particularly, I
guess, to the MRI endpoint, is the number of patients that were
claustrophobic and therefore we couldn't actually perform the
cardiac MRI, and so your primary endpoint ... you missed out. And
so again, there's going to be frustrations like that and a much
larger trial, which will need to involve even more centers. But
funding that's ... for much of the research, I guess, it will be
the challenge, because we've got two agents as Carolyn mentioned
in the beginning that have been around for a long time and are
certainly unlikely to attract any industry funding.


Dr. Carolyn
Lam:              
John, I have a question about the design as well. Of the current
and maybe a future trial, because I'm left with the question, was
it your early intervention? Was it the outcome you chose? Or was
it one drug or the combination? And so, you did not do a
factorial design in this trial. Are there plans to look at that,
or do you the combination ... it's so obvious that two separate
drugs don't need to be tested?


Dr. John
Beltrame:          
Very good question. So, you're quite correct, we can't be
absolutely confident in terms of the mechanism, because we had
one opportunity, I guess, to do the study and so we wanted to
keep a simplified design, and that's what we gave everyone; a
background of nitroglycerin and then just randomized the
N-acetylcysteine. But we think it's actually the combination of
the two that makes the benefits, because as you would be aware,
the synergistic benefits is that the N-acetylcysteine potentiates
the effect of the nitrates, potentiates the vasodilating
properties, potentiates it's anti-platelet properties also. And
so we think it's a combination of the two.


Dr. Laura
Mauri:              
John, it's interesting ... the use of the cardiac MRI endpoint,
as we've all seen, it's being used more and more frequently, but
at the same time, it's new for us, right? So you've raised some
of the challenges and the practical execution of getting patients
who can tolerate it, especially after an acute hospitalization.
But the classical endpoint has been SPECT imaging as a surrogate
endpoint for mortality in myocardial infarction. Of course,
that's based on very large trials showing correlation, but the
MRI should really give much better resolution, so I think that's
really a very logical next step. But I think the more data that
we get across multiple different trials, the better we can
validate that endpoint and see how it might differ from the
classical surrogate endpoints that we've had for myocardial
infarction.


                                               
Other than the efficiency of looking at MRIs, do you have other
observations when you look at MRIs at endpoint compared with some
of the traditional endpoints like SPECT?


Dr. John
Beltrame:          
Not SPECT so much, but to follow on exactly what she was saying,
we all also measured serum creatine kinase, so CK, values. And
because of the larger spread of the data and therefore the need
to have a larger sample size, although we certainly saw a trend
of improvement in CKs as a marker of infarct size, we didn't
achieve statistical significance, but with the MRI because we had
more precise measurements, that gave us a smaller margin of error
and therefore, we were able to see a difference between the two
treatments. So certainly I think in the future, the MRI is
certainly a very good way to evaluate agents in this particular
area.


Dr. Laura
Mauri:              
It's nice to see the consistency that you saw across the
different endpoints.


Dr. Carolyn
Lam:              
That's true, but I do have a question though, as an Echo
cardiologist here, your three-month assessment of the ventricular
remodeling, if I read it right, there was no change detected at
three months. Would you like to comment on that?


Dr. John
Beltrame:          
What we saw in terms of the infarct size, we still saw a
difference. I think what you might be referring to, the infarct
size was a little bit smaller, so that's just ... over time the
we feel like the scar contracts down. But I'm not sure if you're
also referring to the ...


Dr. Carolyn
Lam:              
LV dimensions and injection fraction.


Dr. John
Beltrame:          
The injection fraction's interesting, because when we looked at
that ... because we found no difference in the injection
fraction. Now, if you take a look at the actual values, they're
almost normal and I think that says something to where we are in
terms of the management of acute STEMIs, because we preserved the
left ventricular function, because there were normal ejection
fractions, so we couldn't make them better than what we had in
placebo, so that is something to primary PCI, I think.


Dr. Carolyn
Lam:              
That's a great answer. Thank you, John. And Laura?


Dr. Laura
Mauri:              
John, your group is really to be commended for conducting such a
high-quality trial in this very challenging area. We've been
victims of our own success, I think, in this space because the
mortality rates have obviously declined after MI, infarct size is
on the decline with early reperfusion. Getting in there with
attempted therapies is a race when you're also trying to achieve
fast door-to-ballon times, but it's still an important area and
one we can only address with careful, randomized trials with
important therapies. So I want to congratulate you and your
group, it's really a step in the right direction.


Dr. Carolyn
Lam:              
You've been listening to "Circulation On The Run", thank you so
much for joining us, and don't forget to tune in next week!