Circulation July 10, 2018 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 for the National Heart Center, and Duke
National University of Singapore.


                                               
How do resuscitation teams at top-performing hospitals for
in-hospital cardiac arrest actually succeed? Well, to learn how,
you have to keep listening to the podcast, because we will be
discussing this right after these summaries.


                                               
The first original paper this week tells us that recent
developments in RNA amplification strategies may provide a unique
opportunity to use small amounts of input RNA for genome
wide-sequencing of single cells. Co-first authors, Dr Gladka and
Molenaar, corresponding author, Dr van Rooij, and colleagues from
Hubrecht Institute in Utrecht, the Netherlands, present a method
to obtain high-quality RNA from digested cardiac tissue, from
adult mice, for automated single-cell sequencing of both healthy
and diseased hearts.


                                               
Based on differential gene expression, the authors were also able
to identify multiple subpopulations within a certain cell type.
Furthermore, applying single-cell sequencing on both the healthy
and injured heart indicated the presence of disease-specific
cells subpopulations.


                                               
For example, they identified cytoskeleton-associated protein 4 as
a novel marker for activated fibroblasts that positively
correlated with known myofibroblast markers, in both mouse and
human cardiac tissue. This paper raises the exciting possibility
for new biology discovery using single-cell sequencing that can
ultimately lead to the development of novel therapeutic
strategies.


                                               
Myeloid-derived suppressor cells are a heterogeneous population
of cells that expand in cancer, inflammation, and infection, and
negatively regulate inflammation. However, their role in heart
failure was unclear, at least until today's paper in this week's
journal. Co-first authors Dr Zhou, Miao, and Yin, and
co-corresponding authors, Dr Wang and Li, from Huazhong
University of Science and Technology, measured the
myeloid-derived suppressor cells by flow cytometry in heart
failure patients and in mice with pressure overload–induced heart
failure, using isoproterenol infusion or transverse aortic
constriction.


                                               
They found that the proportion of myeloid-derived suppressor
cells was linked to heart failure severity. Cardiac hypertrophy,
dysfunction, and inflammation were exacerbated by depletion of
myeloid-derived suppressor cells but alleviated by cell transfer.
Monocytic myeloid-derived suppressor cells exerted an
antihypertrophic effect on cardiomyocyte nitric oxide, but
monocytic and granulocytic myeloid-derived suppressor cells
displayed antihypertrophic and anti-inflammatory properties
through interleukin 10.


                                               
Rapamycin increased accumulation of myeloid-derived suppressor
cells by suppressing their differentiation, which in part
mediated its cardioprotective mechanisms. Thus, these findings
revealed a cardioprotective role from myeloid-derived suppressor
cells in heart failure by their antihypertrophic effects on
cardiomyocytes and anti-inflammatory effects through interleukin
10 and nitric oxide. Pharmacological targeting of myeloid-derived
suppressor cells by rapamycin constitutes a promising therapeutic
strategy for heart failure.


                                               
In the FOURIER trial, the PCSK9 inhibitor evolocumab reduced LDL
cholesterol and cardiovascular risk in patients with stable
atherosclerotic disease. However, was the efficacy of evolocumab
modified by baseline inflammatory risk?


                                               
While Dr Bohula from the TIMI Study Group and colleagues explored
this question by examining the efficacy of evolocumab stratified
by baseline high sensitivity CRP. They also assessed the
importance of inflammatory and residual cholesterol risk across
the range of on-treatment LDL concentrations. They found that the
relative benefit of evolocumab for the prevention of adverse
cardiovascular events was consistent, irrespective of baseline
high sensitivity CRP. However, because patients with higher high
sensitivity CRP levels had higher rates of adverse cardiovascular
events, they also tended to experience greater absolute benefit
with evolocumab.


                                               
In an analysis of baseline high sensitivity CRP in achieved LDL
cholesterol, the authors found that at first cardiovascular event
rates were independently associated with both LDL cholesterol and
high sensitive CRP. Event rates were lowest in patients with the
lowest hsCRP and LDL cholesterol, supporting the relevance of
both inflammatory and residual cholesterol risk.


                                               
The next paper provides further evidence that residual
inflammatory risk, as measured by on-treatment high sensitivity
CRP, remains an important clinical issue in patients on
combination statin and PCSK9 inhibitor therapy. Dr Pradhan, from
Brigham and Women's Hospital and colleagues, evaluated the
residual inflammatory risk among patients participating in the
SPIRE-1 and -2 cardiovascular outcome trials, who are receiving
both statin therapy and the PCSK9 inhibitor bococizumab,
according to on-treatment levels of high sensitivity CRP and LDL
cholesterol measured 14 weeks after drug initiation.


                                               
They found that among high-risk stable outpatients treated with
moderate or high-intensity statins and PCSK9 inhibition, roughly
one in two had residual inflammatory risk defined by an
on-treatment high sensitivity CRP level of 2 or more mg per
liters, and roughly one in three had values above 3 mg per liter.


                                               
PCSK9 inhibition was associated with a 60% mean reduction in LDL
cholesterol but little change in high sensitivity CRP. Levels of
high sensitivity CRP above 3 mg per liter were associated with a
60% greater risk of future cardiovascular events, corresponding
to a 3.6% annual event rate, even after accounting for
on-treatment LDL cholesterol.


                                               
Thus, PCSK9 inhibition, added to statin therapy in stable
outpatients, does not lower high sensitivity CRP. Persistent
elevations of CRP is associated with future cardiovascular risk
in these patients, even after low levels of LDL cholesterol are
achieved. If corroborated, these data suggests that inflammation
modulation may yet have a role in the primary and secondary
prevention of cardiovascular disease when LDL cholesterol is
already controlled. Well, that wraps it up for our summaries.
Now, for our future discussion.


                                               
In-hospital cardiac arrests are common worldwide and they're so
important because they represent opportunities for us to improve
survival. Now, yet, overall rates of hospital survival after
in-hospital cardiac arrests remain poor and there is substantial
variation across facilities. This may be surprising because we
all seem to follow or should follow the same ACLS algorithms
across the world and yet, there are different outcomes.


                                               
How do resuscitation teams, at top performing hospitals, for
in-hospital cardiac arrest, how do they succeed? Pleased to be
discussing this with a real star team in today's podcast. We have
first and corresponding author of our feature paper, Dr Brahmajee
Nallamothu. We also have Dr Steven Kronick, who is the chair of
the CPR committee and both are from University of Michigan
Medical School. We also have Dr Sana Al-Khatib, who is a senior
associate editor of Circ, from Duke University. So, welcome
everyone! Let’s go straight into it. Maybe starting with you
Brahmajee, could you tell us what inspired you to perform this
study?


Dr Brahmajee
Nallamothu           
Thank you, Carolyn, for giving us the opportunity to talk about
this study. I'm an interventional cardiologist here at the
University of Michigan and typically, this isn't an area that
interventional cardiologists are really greatly involved with. I
became interested because I also, at times, I round in the
cardiac intensive care unit, and that's a place where a lot of
patients often times end up after they've had an in-hospital
cardiac arrest at our institution and what I've noticed over the
years, is the variability in care that would be occurring out
there, and then also lots of gaps in the literature.


                                               
Over a decade or so ago, I started partnering with a close friend
and colleague, Paul Chan, from the Mid America Heart Institute
and we started to do a series of studies on how in-hospital
cardiac arrest care varies across institutions in the United
States and we published a number of articles that have been in
really high-profile journals over the last 10 years, but the
problem has always been that even though we could describe really
well what was happening, we had very little understanding of why
it was happening or how certain hospitals were seeming to
outperform others in this really challenging situation.


                                               
We wanted to dive a bit deeper into the questions and reasons
behind top performers doing so well and that's what brought us on
to doing this study.


Dr Carolyn
Lam:               
Great. You want to tell us a little bit about it? It's really
very different from the other CPR studies I've seen. Could you
tell us about it and what you've found?


Dr Brahmajee
Nallamothu:         
Sure, so in the broader framework, it's a qualitative study and
what I mean by qualitative is, we didn't really collect data
either through surveys or through outcome assessments. What we
did was, we actually went out and talked to people.


                                               
The study though was really focused on what people call a mixed
methods approach. We didn't just randomly talk to different
hospitals, we actually focused on hospitals that were at the
top-performing levels. We also focused on some hospitals that
were non-top-performing as well, to get some contrast between the
two and when I said we talked, we did this in a very systematic
and pretty rigid way.


                                               
We always had four interviewers go out to nine hospitals. We
split them up, so we had two content experts and then two
methodologic experts in qualitive studies, and we started to
interview a bunch of people. In fact, we interviewed almost 160
people across these nine hospitals.


                                               
We interviewed everyone from CEOs and hospital leadership, down
to boots on the ground, including both clinical providers and
even non-clinical providers, such as spiritual care, security. We
tried to get this comprehensive view of what was actually
happening during an in-hospital cardiac arrest across these nine
hospitals, and really the results were quite fascinating to us.


                                               
For someone, like myself, that's been in this space for ten
years, I tell people I learn more talking to these nine hospitals
than I have in the last ten years of looking at numbers on a
spreadsheet. I really started to understand, for the first time,
what was really going on, how these hospitals were dealing with
these challenging situations because there's no bigger emergency
in a hospital, and Steve, who we're going to hear from, we talk
about this, but Steve has a great line about how when an
in-hospital cardiac arrest occurs, that patient automatically
becomes the sickest person in an institution and yet, we haven't
set up systems that really build on how to handle that in the
most consistent and positive way.


Dr Carolyn
Lam:               
Oh, my goodness, I just love that line! Now, you have to tell us,
so what's the secret? What's the secret of the succeeding
hospitals?


Dr Brahmajee
Nallamothu:         
What we found in general was, that resuscitation teams at
top-performing hospitals really demonstrated the following
features. They had dedicated or designated resuscitation teams.
They really included the participation of diverse disciplines as
team members during the in-hospital cardiac arrest. There were
really clear roles and responsibilities of the team members that
were set up right from the front.


                                               
There was better communication and leadership, actually, during
these events and finally, in the training aspect, one of the
unique things we found was, the top-performing hospitals seem to
have a high rate of in-depth mock codes, that they used as
strategies for getting their clinicians ready for these events.


Dr Carolyn
Lam:               
As you were speaking I was just thinking through the experiences
of in-hospital cardiac arrests that I've encountered, and you're
right. These elements, though we don't talk about them much, make
a huge difference. Steve, I am so curious about your outlook. I
mean you must have attended a kajillion CPRs as chair of the CPR
committee. Tell us, what do you think is the take home message
for clinicians and hospitals?


Dr Steven
Kronick:          
My field is in emergency medicine and as chair of the CPR
committee, I have responsibility of overseeing how we respond to
cardiac arrests in our hospitals. I think that many institutions
spend a lot of time and effort looking at in-hospital cardiac
arrests are managed, and how to improve on it. We're able to use
data to help compare ourselves to similar institutions, but
beyond the bottom line of either ROSC or survival to discharge,
we've most relied on process measures to figure out what we're
doing.


                                               
We're essentially flying blind, or at least not flying in any
sort of formation when we do that. I think that this study
validates some of the operational aspects of the arrest response,
for those centers who use those and can help other decide where
they want to direct their efforts. I think a good example that
Brahmajee brought up, is this distinction we found between the
use of dedicated teams, designated teams, or not having any
organized team, and the impact that has on survival.


                                               
The use of these teams can mean significant use of resources but
showing that it's associated with better outcomes help provide
support for that concept and for those centers who might already
use one of those models, it helps them to steer their efforts to
improving the delivery or the efficiency of that model.


Dr Carolyn
Lam:               
Yeah, and indeed. Congratulations to both of you, Steve and
Brahmajee. I do think that these are novel contemporary data, at
least the first that I know of. Sana, you handle the paper and
recognize this. Could you tell us a little about what you think
are the novel and important aspects?


Dr Sana
Al-Khatib:           
I really have been a fan of this paper from the get go and yes,
it doesn't have the quantitative analysis that the statistical
modeling, most of us are used to. It is a qualitative study, but
I think that gives it strength. It makes it unique. This type of
research, it can really only be effectively done through a
qualitative study that really has all the important aspects of a
good qualitative study, so I do want to congratulate them.
Clearly, a lot of work went into this, and I appreciate all their
efforts.


                                               
In terms of the main findings, some of us might look at this data
and say, well it's not surprising that those are the
characteristics, or the features, of the top performing
hospitals, but I felt like it was great, in terms of how the data
were presented. Encouraging hospitals to adopt this. Giving them
almost like a checklist of what they need to be doing to improve
the outcomes of their in-hospital cardiac arrests, in terms of
ensuring that they have designated resuscitation teams.


                                               
The whole idea about diversity of participants in these arrests,
and making sure everyone has a clear role and responsibility. The
whole idea of making sure that somebody takes leadership and you
have clear and very good communication among the different people
who are doing this and great training. In fact, these people were
doing in-depth mock codes. I think that spells it out very nicely
and gives a lot of the hospitals, hopefully, action items that
they can implement to improve the outcomes these patients. I love
this paper.


Dr Carolyn
Lam:               
Sana, I love the way you put that. Checklist, and you know what I
was thinking as Brahmajee and Steve were talking earlier? I was
thinking blueprint, almost, of the things that we should have. So
Steve, could I ask your thoughts. I mean, are you going to put
some of these things into practice in your own committee and how?


Dr Steven
Kronick:          
There are a variety of things we can do. Some of these things are
a pretty high-functioning place, but still looking at
recommendations that have been laid out and how we help modify
those things. Though the example is the roles that people play at
an arrest. We can certainly improve on assigning those roles, how
people work together as a team, and then also, getting to work
more as a team, so that when they are called upon to perform
those duties, they can do it in a more coordinated way.


Dr Carolyn
Lam:               
How beautifully put. I'm going to steal a couple of minutes at
the end of this podcast. I really have to because it's so rare to
have Brahmajee on the line today and he's the Editor-in-Chief of
Circ: Cardiovascular Quality and Outcomes. Brahmajee, could I ask
you to say a few words to our worldwide audience about your
journal?


Dr Brahmajee
Nallamothu:         
We are a kind of daughter journal to Circulation. We are a bit
more unique than the others, in the sense that we aren't disease
or subspecialty focused. We deal with, broadly, the issues around
outcomes research, health services research, quality of care
research, and really health policy. We publish an issue once a
month. We have a broad interest in things that are really
relevant to the community around outcomes research and health
services research.


                                               
I will say that I really appreciate this because of the worldwide
audience and reach, one of the big issues we've been very
interested in is expanding our reach, from the United States to
other parts of the world, and in fact, last fall, we had a global
health issue, which was well received, and we received papers
from across the world.


                                               
In fact, every paper in that issue was a non-US-based paper, and
it touched on a number of things from issues around healthcare
utilization in Asia to demographics and disease registries in
Africa, and it was a wonderful experience, so I think it's a
journal that we're excited about.


                                               
It was first launched by Harlan Krumholz, who has set a high bar
and standard for us, and I think that my editorial team, which
has been fantastic, has continued with that work. We would love
to see papers from your readers and your listeners from across
the world and excited about what that journal is going to be
doing in the next five years.


Dr Carolyn
Lam:               
Oh wow! That's so cool! Well listeners, you heard it right here,
first time on Circulation on the Run. Thank you so much for
joining us today. Don't forget to tune in again next week.