Circulation March 5, 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 doctor
Carolyn Lam, associate editor from the National Heart Center, and
Duke National University of Singapore.


Dr Greg
Hundley:            
And I'm Greg Hundley, associate editor from the Pauley Heart
Center at VCU Health in Richmond, Virginia.


Dr Carolyn
Lam:               
Have you heard of long non-coding RNAs? Well, they are definitely
the hot topic and our feature paper today discusses the first
demonstration of the importance of a linked RNA in
atherosclerotic lesions not just in mice but also in humans. You
have to listen on, it's coming up right after our copy chat.


                                               
Greg, what are your picks upon the journal this week?


Dr Greg
Hundley:            
The first paper I wanted to discuss comes from France, and it's
basically looking at ambulance density and outcomes after out of
hospital cardiac arrest from Florence Dumas from Hôpital Cochin
in Paris, France. This manuscript addresses the geographic
disparities and survivorship of out of hospital cardiac arrest
and the relevance of the patients characteristics versus whether
ambulances are equipped with those trained in basic or advanced
cardiac life support. So, what they did they had nineteen
neighborhoods in Paris, and the number of BLS trained versus ALS
ambulances was collected, and the authors assessed that
respective associations of socio-economic characteristics of the
patient population and the ambulance resources of these
neighborhoods and compared those with successful return of
spontaneous circulation or risk as the primary end point and then
survival of out of hospital discharge as the second end-point.


                                               
So, they had 80754 non-traumatic out of hospital cardiac arrests
across the Paris area. 42% at ROSK 9% head survival at discharge,
and after accounting for the patient's socio-economic status,
greater than one and a half advanced cardiac life support
ambulances per neighborhood and greater than 4 basic cardiac
support basic life support units per neighborhood were associated
with ROSK, but only the 1.5 ALS units per neighborhood were
associated with survival.


Dr Carolyn
Lam:               
Oh, interesting Greg. So does this we need more advanced life
support units?


Dr Greg
Hundley:            
So, Paul Dorian from St. Micheal's Hospital in Toronto, Canada
wrote an excellent editorial, and one point he made related to
these ALS units is that it was really a very small 1.3 adjusted
odd ratio for survival to hospital discharge, and it's important
to note that although the increase in survival was associated
with more ALS units, there were many other variables that were
likely important and not recorded in this study. For example,
including the time to collapse, to calling for EMS, the time from
the call to the deployment of that ALS unit to the scene, the
time from collapse to the defibrillation, the total "no flow
time" sort of in quotation, which is the total duration of
collapse until CPR is started and so I think one of the points in
this observational study is there could've been many differences
that would've associated with the findings, interesting findings
how about one of the papers that you liked?


Dr Carolyn
Lam:               
So, the paper that I selected here is a first time that a
targeted anti-inflammatory therapy has been shown to reduce
hospitalization for heart failure and at-risk patients. So, you
know that some clinical inflammation associates with an increased
risk of heart failure and associates with the worst prognosis in
patients with heart failure, and yet, so far, treatments
specifically directed at reducing inflammation in patients with
heart failure have not been shown to improve clinical outcomes.
That's why today's paper is so special and it's from Dr Everett
and colleagues from Brigham and Women's Hospital Harvard Medical
School in Boston, and basically, the authors looked at CANTOS and
tested the hypothesis that the interleukin -1β inhibitor can
canakinumab would prevent heart failure hospitalizations and the
composite of heart failure hospitalizations on heart failure
related mortality in the CANTOS trial.


                                               
Now, remember the CANTOS trial randomized more than 10 000
patients with a prior myocardial infarction and with high
sensitivity C-reactive proteins at least two or greater, and they
were randomized to canakinumab 50, 150, and 300 mg or placebos.
Now, before randomization, these participated were asked if they
had a history of heart failure and 22% said yes so the current
paper actually looks at this stratification of patients who said
they had heart failure, and during a meeting follow-up of 3.7
years, 385 patients had a new heart failure hospitalization
event. Now, here's the key: the authors found a dose dependent
reduction in the risk of hospitalization for heart failure as
well as the composite of hospitalization for heart failure or
heart failure related mortality among those allocated to
Canakinumab.


Dr Greg
Hundley:            
So, how does this differ from prior attempts targeting
inflammation and heart failure? I mean is this ready for prime
time thing?


Dr Carolyn
Lam:               
So, we have to bear a few things in mind here you know. CANTOS
was different from a previously published randomized controlled
trials, which were basically neutral and that was like of
infliximab and etanercept so the drug in CANTOS targets
interleukin-1 beta whereas the prior ones targeted the TNF-alpha,
and also very importantly, CANTOS did not specifically enroll
patients with an established heart failure only. CANTOS patients
had to have a history of myocardial infarction and there was no
data on their ejection fraction or natriuretic peptides at the
time of randomization nor at the time of heart failure
hospitalization. So, by the way, we don't know whether there's a
differentially effect on hep pef versus hep-ref. So, again
difference from the heart failure focused trial previously that
used an anti-inflammatory agents.


                                               
The other thing: although there was a dose dependent reduction in
the risk of hospitalization for heart failure no single dose of
Canakinumab compared to the placebo had a statistically
significant reduction in the risk of heart failure
hospitalization. Only the trend was statistically significant so
all in all, this was a pre-specified aim of CANTOS to look at
heart failure, the data presented here should really be
considered hypothesis generally, but really quite promising. And
what about you Greg? What's your other paper?


Dr Greg
Hundley:            
We're going to switch gears a little bit and shift over to the
Jackson heart study. The large longitudinal cohort from Jackson,
Mississippi that's recruited to follow for cardiovascular events,
and it's an area of the United States where we have some of the
highest cardiovascular disease event rates really across the
nation so this study focuses on sleep apnea and is the Jackson's
heart sleep study. It's a sub-study of this larger Jackson's
heart study that involves 913 patients, and the investigators
were looking at the association between sleep apnea and blood
pressure control among those of a Black race. So, Dayna Johnson
of Emerald University is the first author on the paper. What's
nice about this sub-study, this sleep sub-study is that there are
objective measures using an in-home type III sleep apnea study.
They had clinical blood pressure measurements and then
anthropometry as opposed to questionnaire derived data that may
have been performed in the larger cohort.


                                               
And the study determined these associations between moderate or
severe obstructed sleep apnea with controlled, uncontrolled and
resistant hypertension. So the analytic sample of the individuals
with hypertension was 664, and they had an average age of about
64 years. They were predominately women 69%, obese 58%,
College-educated at 51%. Among the sample, about a quarter had
obstructive sleep apnea, which was untreated and unrecognized in
94% of the participants. That's an interesting point, just right
there.


                                               
Overall, 48% of the participants had uncontrolled hypertension
and 14% had resistant hypertension. So, multiple medications,
often four and still unable to control the blood pressure. So the
findings participants with moderate or severe obstructive sleep
apnea had 2 times higher odds' ratio of resistant hypertension.


Dr Carolyn
Lam:               
Whoa Greg, that's a huge risk and very important finding. I mean
if sleep apnea could be modifiable risk factor perhaps for very
important issue among African Americans resistant hypertension.
What do you think about clinical implication?


Dr Greg
Hundley:            
One of the things to be considering now is what are we going to
do about that cause as you know CPAP is really the preferred
treatment for resistant hypertension, but it's efficacy hasn't
been really that well studied in African Americans and CPAP
tolerance is low so this study highlights for us potentially new
mechanisms for resistant hypertension, but we still got to be
thinking about what would be our next therapeutic intervention
for this particular patient population. And what about your next
study?


Dr Carolyn
Lam:               
The next study is about Impella support for acute myocardial
infarction complicated by cardiogenic shock. Now, we use it all
the time, but did you know that to date, there is no large
randomized study actually comparing the use of Impella to other
contemporary cardiac support devices and medical treatment in
stem related cardiogenic shock. So, Dirk Westermann and
colleagues from University Heart Center in Hamburg tried to
address this knowledge gap by using a multi-national database of
patients with acute myocardial infarction complicated by
cardiogenic shock and treated with the Impella device and
compared in a matched fashion their outcomes to patients from the
IABP Shock II trial, which you would recall is a randomized trial
which demonstrated similar outcomes between IABP and medical
treatment in myocardial infarction in cardiogenic shock.


                                               
So, they looked at 237 matched-pairs so remember this was pairs
from this registry of acute myocardial infarction with shock and
using an Impella matched with IABP shock patients and what they
found was that there was no significant difference in 30-day
all-cause mortality. Instead, severe or life-threatening bleeding
and peripheral vascular complications occurred significantly more
often in the Impella group when they limited the analysis to the
IABP treated group as controlled versus Impella that was still
the same results.


Dr Greg
Hundley:            
So, Carolyn, there are trying to match patient population from
two different studies and they may have confounders in there that
we can't account for so why we not able to produce large
randomized trials of Impella devices in studies of patients with
acute myocardial infarction?


Dr Carolyn
Lam:               
The rate of acute myocardial infarction complicated by
cardiogenic shock has really declined in the past decade.
Furthermore, clinical signs of shock really appear in half to
three quarter of cases several hours after hospital admission so
making randomization before primary PCI of the AMI really very
difficult. And finally, many interventional cardiologists believe
that there's equipoise that has already been reached on the use
of these cardiac assistive devices in patients with cardiogenic
shock and this was from registry data, and so if interventionists
believe this then they also believe its unethical to randomize
these patients in trials. Still, I think that current study to
date really causes us to pause and to acknowledge that we really
need to evaluate this better and prospective randomize trials of
Impella treatment are warranted.


                                               
Let's now go to our featured discussion, shall we?


                                               
For our featured paper discussion today, we are talking about a
basic science paper, and we have none other than the best of the
best Dr Charles Lowenstein, our associate editor from University
of Rochester Medical Center joining us as well as the first
author of a really fantastic paper on long non-coding RNA in a
specific type involved in arthrosclerosis and plaque formation.
This first author is Sebastian Creamer from Goethe University in
Frankfurt.


                                               
Charlie, could you start us off by telling us what is a long
non-coding RNA? We've heard a lot about this in recent times.
What's the big deal about them?


Dr Charlie Lowenstein:  So in the last decade, scientists
have learned that your genome, your DNA inside you, every cell
codes about 20,000 genes and those 20000 genes encode proteins,
but there are another 20000 genes that encode RNA only, RNA that
never turns into protein that leaves RNA are an amazing diversity
of different kinds of RNA really short micro RNA, longer RNA that
defends the host from viruses and long non-coding RNA that have a
huge variety of effects regulating genes, turning genes on and
off in proliferation and cell growth and inflammation so long
non-coding RNAs are increasingly appreciated as an important part
of the genome.


Dr Carolyn
Lam:               
What a perfect set up with that. Sebastian, could you tell us
about your study please?


Dr Sebastian Creamer:   Our laboratory was interested
in non-coding RNAs for some time and previously, we've found that
this specific non-coding RNA MALAT1 regulates endothelial cell
functions and because we were interested in analyzing this
particular RNA in the disease setting it shows at a risk growth
so it's because also we saw that when it's regulated by flow and
end of previous cells and so we cross MALAT1 deficient mice to
Apoe mice and set them on a high fat diet and analyzed and
subtracted in both groups. And while we only saw a modest
increase in plaque size in MALAT1 deficient mice, we could
appreciate a higher amount of inflammatory cells in plaque of
aortic roots in those mice, which let us hypothesize that
inflammatory responses was appreciated and is a very important
contributor to arthrosclerosis in MALAT1 deficient mice. And to
test this, we decided to transplant MALAT1 deficient bone marrow
in Apoe knockout mice with MALAT1 and interestingly, we saw that
now plaques were significantly larger than compared to mice who
received controlled MALAT1 white cell bone marrow, and also
inflammatory cells were more prominent in those mice.


Dr Greg
Hundley:            
Sebastian, this is Greg Hundley. You also did some experiments in
human subjects. Could you tell us a little bit about those too?


Dr Sebastian Creamer:   So, because we saw this
interesting phenotype, we were very much interested if this also
translates into the human setting. Luckily, we got a really nice
collaboration receding in Stockholm access to high impact
material from patients with arthrosclerosis and what we could see
here that MALAT1 expression was down regulated in patients with
arthrosclerosis and it also correlated with disease progression.
Moreover, in another collaboration, we consolidated those
findings with experiments, which showed that human cells have
less MALAT1 compared to normal vasculature.


Dr Carolyn
Lam:               
It all sounds so sensible and logical and so on but let me just
frame this for our audience. This is actually the first time that
it's been demonstrated. The importance of long non-coding RNA in
arthrosclerosis. Charlie, could you tell us a little bit about
how significant these findings are?


Dr Charlie Lowenstein:  Sure. So, I'm really interested in
the final figure in this paper because there are lots of
interesting human data, showing that MALAT1 expressed more in
normal than atherosclerotic arteries and also that MALAT1
expression is correlated with fewer major adverse cardiac events
so the whole story is a very nice story saying that the
expression of this anti-inflammatory link RNA not only has an
effect in mice but it can be extended into the human field of
arthrosclerosis and inflammation. It's particularly important
because there's a lot of attention in the last decade that
inflammation drives atherosclerosis, and in light of CANTO trial
showing that anti-inflammatory therapy can actually decrease
atherosclerosis and decrease cardiovascular events in humans.
This is important cause it shows another pathway, which regulates
inflammation. Not only in mice, but also in humans, and in the
human atherosclerotic setting.


Dr Carolyn
Lam:               
Amazing. Sebastian, what are the next steps? How far are we away
from clinical applications here? What are the next steps to get
it in the clinic?


Dr Sebastian Creamer:   So, the very difficult thing is
that MALAT1 is down-regulated in atherosclerosis and also
therapeutic approaches is very difficult in such a complicated
disease like atherosclerosis to actually increase the expression
of such a long non-coding RNA. What we are currently working on
is to decipher more than the clinical malade-1 is actually
influencing atherosclerosis so we have lots of hints or some
evidence that adhesion of inflammatory substances altered and the
bone marrow activity, which is very important in atherosclerosis
and also in other cardiovascular diseases like myocardial
infarction is altered so we think that malade-1 might actually
influence the resolution of inflammation and when it's lacking,
inflammation can be resolved. So, we are now putting somewhat
mechanistic studies and finally, we hope that we can find another
downstream target like micron AB, we talked about in our paper,
which we can directly target in the future.


Dr Charlie Lowenstein:  So, I agree with Sebastian. I think
MALAT1 is going to turn out as one of those major link RNAs that
controls inflammation possibly controlling the way in which the
bone marrow reacts to systemic inflammation and produces cells
and then have those cells home in on various inflammatory targets
so I think this is an important observation that's going to have
not only implications for atherosclerosis but also for other
inflammatory diseases.


Dr Carolyn
Lam:               
Excellent. If you don't mind, I would love to switch tracks a
little bit. We find it that very special and we can discuss basic
papers with people who can explain it so well because we
understand that there's so much work that goes in to these papers
and so on. Charlie, could you take behind the scenes a little bit
with the editors and tell us what is it that circulation looks
for in basic science papers that makes us published?


Dr Charlie Lowenstein:  We get a lot of really good basic
science papers, and it's a challenge for the associate editors,
and the editors to figure out what's right for circulation and
let me use this manuscript as a great example because this is a
terrific paper. So, this paper is divided into four sections, and
these sections are what we look for in any basic science paper
that's going to reach an audience of clinicians who are
interested in pathways and therapeutics so this paper has a
section on mice. There's a gene in mice that's important then the
paper delves into cells what's happening with cells and then a
little bit of mechanisms and genes and proteins and then this
paper takes the observation back into humans and shows that
there's some human and clinical relevance so this is not only a
great paper, but it is a classic example of what the associate
editors are looking for in a basic science paper that's targeted
towards clinicians.


Dr Charlie Lowenstein:  There's some in vivo work with mice,
there's some mechanistic work then they take it back to the
humans. Plus, of course like anything that comes into
circulation, it's going to be novel, interesting and has some
important relevance to human cardiovascular disease. This paper
that we're discussing is a great example of a paper that we love
to publish in a circulation and it's a real tribute to Dr
Dimmeler and her team and to Sebastian that they put this paper
together and submitted it to us.


Dr Carolyn
Lam:               
Thank you audience for joining Greg and I today. You've been
listening to circulation on the run. Don't forget to tune in
again next week.