Circulation November 27, 2018

Dr Carolyn
Lam:               
Welcome to Circulation on The Run, your weekly podcast summary
and backstage pass to the journal and it's editors. I'm Dr
Carolyn Lam, Associate Editor from the National Heart Center and
Duke National University of Singapore. We will be discussing
accelerated diagnostic protocols for chest pain, a very, very
important issue in Cardiology with very important new safety and
effectiveness data on one such protocol provided in our feature
paper this week. Coming right up after these summaries.


                                               
Our first original paper this week identifies a new link between
specific gut bacteria and atherosclerosis. Co-First authors, Dr
Yoshida and Emoto, corresponding author, Dr Yamashita, from Kobe
University Graduate School of Medicine, and colleagues recruited
patients with coronary artery disease and controls without
coronary artery disease but with coronary risk factors. They then
compared gut microbial composition using 16S ribosomal RNA gene
sequencing in fecal samples. Subsequently, they used
atherosclerosis prone mice to study the mechanisms underlying the
relationship between such species and atherosclerosis. Their
analysis of gut microbial profile in patients with coronary
artery disease showed a relative depletion of bacteroides
vulgatus and bacteroides dorei compared to controls with coronary
risk factors. Gavage with live bacteroides vulgatus and
bacteroides dorei decreased fecal and plasma lipopolysaccharide
levels and protected against atherosclerosis in apoE deficient
mice. Fecal lipopolysaccharide levels in patients with coronary
artery disease were significantly higher compared to controls.
These findings suggest that bacteroides treatment may serve as a
novel and effective therapeutic strategy for suppressing
lipopolysaccharide-induced inflammatory response in coronary
artery disease.


                                               
The next paper identified a potential novel molecular target in
the treatment of myocarditis. Co-First authors, Dr Chen and Zeng,
Co-Corresponding authors, Dr Song from Fuwai Hospital in Beijing,
and Dr Yang from Shenzhen University School of Medicine, and
their colleagues aim to elucidate the role of BCL2 Like protein
12 in the pathogenesis of biased T Helper-2 response in
myocarditis. Using a combination of mouse models of myocardial
inflammation and human hearts from patients undergoing heart
transplantation, the authors found that CD4 positive T-cells
isolated from hearts in myocarditis at the end stage of heart
failure expressed high levels of BCL2 Like protein 12, which was
required for the development of aberrant T Helper 2 polarization
in the heart. Thus, BCL2 Like protein 12 may be a novel target in
the treatment of myocarditis, as well as other T Helper 2 biased
inflammatory processes.


                                               
Could vaccination against LDL be a way to prevent
atherosclerosis? Well, the next paper brings us one step closer
to this dream. First author, Dr Gisterå, corresponding author, Dr
Hansson from Karolinska School University Hospital and colleagues
developed T-cell receptor transgenic mice to study LDL
autoimmunity in a humanized hypercholesterolemic mouse model of
atherosclerosis. A strong T-cell dependent E-cell response was
induced by ODL leading to production of anti-LDL IgG antibodies
that enhanced LDL clearance and ameliorated atherosclerosis.
Results show that anti-LDL immuno-reactivity evoked three
atheroprotective mechanisms, namely 1) antibody-dependent LDL
clearance, 2) increased cholesterol excretion, and 3) reduced
vascular inflammation, thus targeting LDL-reactive T cells may
enhance atheroprotective immunity, and vaccination against LDL
components may be an attractive way to prevent atherosclerosis.


                                               
MicroRNAs regulate nearly all biological pathways and
dysregulation of MicroRNAs is known to lead to disease
progression. However, are there cell type specific effects of
MicroRNAs in the heart? Co-First authors, Drs Rogg and Abplanalp,
corresponding author, Dr Dimmeler from Goethe University
Frankfurt, and colleagues assessed MicroRNA target regulation
using MicroRNA 92a3p as an example. Their data showed that
MicroRNAs have cell type specific effects in vivo which would be
overlooked in bulk RNA sequencing. Analysis of MicroRNA targets
in cell subsets disclosed a novel function of MicroRNA 92a3p in
endothelial cell autophagy and cardiomyocyte metabolism. These
findings may have clinical applications for the fine tuning of
autophagy and metabolism to mitigate tissue damage in patients
with cardiac disease.


                                               
The next paper establishes a mechanism by which cardiac
inflammation may be initiated in response to hemodynamic stress,
but in the absence of significant cardiomyocyte cell death.
Co-First authors, Drs Suetomi and Willeford, Co-Corresponding
authors, Drs Brown and Miyamoto from University of California San
Diego, and their colleagues used conditional
cardiomyocyte-specific calcium calmodulin-regulated kinase Delta
all CaM kinase II Delta knockout mice to demonstrate that
cardiomyocytes generate inflammatory chemokines and cytokines and
are the initial site of NLRP3 inflammasome activation. They
further identified a causal role for CaM-Kinase II Delta-mediated
activation of NLRP3 inflammasome and inflammatory responses in
macrophage recruitment, cardiac fibrosis, and development of
heart failure induced by pressure overload. Their elegant mouse
experiments revealed sites and mechanisms of proinflammatory gene
and inflammasome activation within cardiomyocytes which could
serve as targets for early intervention or disease prevention.


                                               
Are there different metabolomic effects between PCSK9 inhibitors
and statins? First author, Dr Sliz, Corresponding Author, Dr
Würtz from Nightingale Health Limited in Helsinki, Finland, and
their colleagues quantify 228 circulating metabolic measures by
Nuclear Magnetic Resonance Spectroscopy for over 5300 individuals
in the PROSPER Trial at six months post randomization. The
corresponding metabolic measures were also analyzed in eight
population cohorts, including more than 72,000 individuals using
a specific PCSK9 inhibitor SNP as an unfounded proxy to mimic the
therapeutic effects of PCSK9 inhibitors. Scaled to an equivalent
lowering of LDL cholesterol the effects of genetic inhibition of
PCSK9 on these 228 metabolic markers were generally consistent
with those of statin therapy. Alterations of lipoprotein lipid
composition and fatty acid distributions were also similar.
However, discrepancies were observed for very low-density
lipoprotein or VLDL lipid measures where genetic inhibition of
PCSK9 had weaker effects on lowering VLDL cholesterol compared
with statin therapy. Genetic inhibition of PCSK9 showed no
significant effects on amino acids, ketones, or a marker of
inflammation, where a statin treatment weekly lowered this marker
of inflammation. Thus, if VLDL lipids have an independent causal
effect on cardiovascular disease risk, the observed discrepancy
on VLDL lipid lowering could contribute to differences in
cardiovascular risk reduction between statins and PCSK9
inhibitors for an equivalent reduction in LDL cholesterol.
Moreover, these results exemplify the utility of large-scale
metabolomic profiling with genetics and randomized trial data to
uncover potential molecular differences between related
therapeutics.


                                               
The final original paper this week demonstrates a novel biomarker
discovery paradigm to identify candidate biomarkers of
cardiovascular and other diseases. Co-First authors, Dr Mosley
and Benson, co-corresponding authors, Dr Wang from Vanderbilt
University Medical Center and Gerszten from Beth Israel Deaconess
Medical Center, and their colleagues employed a virtual proteomic
approach linking genetically-predicted protein levels to clinical
diagnosis in more than 40,000 individuals. They used genome-wide
association data from the Framingham Heart Study to construct
genetic predictors for more than 1100 plasma protein levels. They
validated the genetic predictors for 268 proteins and used them
to compute predicted protein levels in more than 41,000 genotyped
individuals in the eMerge Cohort. They tested associations for
each predicted protein with more than 1100 clinical phenotypes.
These associations were validated using directly-measured protein
levels and either LDL cholesterol or subclinical atherosclerosis
in the Malmo Diet and Cancer study. Using this virtual biomarker
strategy the authors identified CLC1B and PDGFR Beta as potential
circulating biomarkers of atherosclerosis and validated them in
an epidemiologic cohort. Thus, these results demonstrate that a
virtual biomarker study may efficiently identify potential
biomarker disease associations, and that wraps it up for our
summaries. Now for our feature discussion.


                                               
Accelerated diagnostic protocols for testing are used everywhere.
They're designed to improve the quality and value of chest pain
risk stratification. However, many of them lack sufficient
prospective safety and effectiveness data. We're so pleased to
have a paper today that provides such important data on one of
these accelerated diagnostic protocols for chest pain, and it's
the HEART Pathway. To discuss this, I've got the corresponding
author of today's featured paper, Dr Simon Mahler from Wake
Forest School of Medicine, as well as our Associate Editor, Dr
Deb Diercks from UT Southwestern. Simon, could you start by just
telling us, what is the HEART Pathway?


Dr Simon
Mahler:            
Sure. Yeah, it's an accelerated diagnostic protocol. It's based
on an accelerated diagnostic protocol called the HEART Score. We
use a modified version of the Heart Score. We actually use a HEAR
score, and that stands for the history, EKG, Age, and risk
factors. That is combined with two troponin measures at 0 and 3
hours. We also factor in whether or not the patient has had prior
coronary artery disease or has an acute ischemic EKG. So, to be
low-risk you have to have a HEAR score of 0-3. HEAR is an
acronym. You get points for each of those categories. If you have
less than 3 points that's a low score. You have to have a low
score, a non-ischemic EKG, no history of prior coronary disease,
and two troponins less than a 99th percentile at 0 and 3 hours to
be considered low risk and recommended for early discharge. If
you don't meet any of those criteria then you are considered
non-low risk and appropriate for further in-hospital evaluation.


Dr Carolyn
Lam:               
That's great. Could you just tell us what you did to give us some
real-world safety and effectiveness data on this.


Dr Simon
Mahler:            
Yeah, so we had done a single-site randomized controlled trial.
That was published in 2015 in Circulation: Quality and Outcomes,
and really showed some promising results. We received some
funding to do an implementation trial. So, this is the results of
our implementation study. It's a before and after study. What we
did was we sought to implement a HEART Pathway as a clinical
decision support tool, integrated fully into our electronic
medical record so that when providers see the patient with chest
pain and order a troponin they interact with a HEART Pathway tool
that guides them through the HEART Pathway risk assessment and
then provides real-time decision support regarding their
treatment and disposition decisions based on whether or not the
patient has a low-risk assessment or a non-low-risk assessment.
The design of the study was we collected data on all patients
with chest pain and troponin order for one year while we worked
on how we were gonna build this tool and embed it, and then we
had three month watching period where we built the tool into the
electronic health record across our three sites. Then, we had one
year where we were post implementation where we collected data
and looking at the difference in outcomes, particularly looking
at both safety and utilization outcomes before and after use of
the HEART Pathway.


Dr Carolyn
Lam:               
That's just such a clever design. Just give us a summary of the
results before I ask Deb to chime in here.


Dr Simon
Mahler:            
There's a few really important things that we found. Probably the
most important thing was the safety data that came out of this
study. We had some good safety signals on prior studies. They
didn't have enough sample size to really have a good precision
around the safety point estimate, so in this study we had over
4000 patients in our post-implementation cohort, and about 31%,
30.7%, of those patients were classified as low-risk by the HEART
Pathway. Among those patients that were classified by low-risk,
the rate of death and MI, the composite outcome at 30 days, was
0.4%. Typically for these accelerated diagnostic protocols we
want them to have an adverse cardiac event rate less than 1%, so
a finding of 0.4% with a confidence in our role that doesn't
extend beyond 1% that was a really important finding that really
confirms the safety of this strategy.


                                               
The other thing that we found which was interesting was that the
use of the HEART Pathway was actually associated with detecting
more myocardial infarctions during the index visit, which means
that possibly the HEART Pathway use improved the recognition of
those patients that were presenting with MIs. It's possible that
without using the HEART Pathway some of those cases may have been
missed. Finally, we were able to demonstrate that use of the
HEART Pathway as a clinical decision support tool was able to
decrease hospitalizations and some other utilization metrics such
as stress testing and possible length of stay.


Dr Carolyn
Lam:               
Oh, that's awesome, Simon. I said it earlier. I'm gonna say it
again. Thank you so much for publishing this wonderful work with
Circulation. I really think that implementation, science, and
decision support tools you've got that all in this paper, just
beyond even the actual topic. Deb, take us behind the scenes a
little bit with how we reacted as editors to this paper, please.


Dr Deb
Diercks:                
Well, I think that overall, we were really excited about this
paper. It really does add a real, real context to something we
were really discussing and wondering about. I think one of the
great things about the implementation, and Simon, please comment
on this, is the diversity of the places that you actually used
this in. I mean, most of us when we look at papers there's always
a fear that it won't be able to be generalized to real-world
practices. Correct me if I'm wrong, but you really applied it to
just a wide variety of Emergency Departments that really support
that this could be used anywhere.


Dr Simon
Mahler:            
Yeah, I think that's a really important point, that we did this
across our system so that included a large academic busy
Emergency Department that sees over 100,000 patients per year,
all the way, basically to a smaller 12,000 per year, essentially
almost a free-standing Emergency Department at the time that we
started our study; it now has inpatient bed capacity, and then a
suburban/rural hospital, as well, with about 30,000 patient
visits per year. We extended beyond kind of the typical kind of
comfort zone of large academic centers and into smaller community
Emergency Departments as well.


Dr Deb
Diercks:                
One of the things that this manuscript nicely articulated is that
you kind of break it into the HEAR and then the troponin.


Dr Simon
Mahler:            
Right.


Dr Deb
Diercks:                
Things change in the US with troponin. How do you think that's
gonna impact how you guys apply this Pathway in the future?


Dr Simon
Mahler:            
It's a big topic of discussion right now, what to do with these
Pathways. Are these Pathways still needed with the availability
now of high-sensitivity troponins in the United States? I think
that for many years as we've kind of followed data coming out of
Europe we've been anxiously awaiting the arrival of these tests
in the U.S., and there's a lot we can learn from the European
data so far. Most of that data suggests that the high-density
troponins are best used still in the context of a Pathway or an
accelerated diagnostic protocol.


                                               
I think that this particular study was conducted just using
contemporary troponins, particularly given the time frame of the
study in which we were accruing patients from 2013 through 2016,
but I think it's still gonna be highly relevant, because I think
that best practices are gonna still require us to use some sort
of structured framework with high-sensitivity troponins. Now, it
does remain to be seen a little bit what the best Pathway is
gonna be to incorporate that. My take on this is that I believe
that clinical decisions support tools or decision aids integrated
with high-sensitivity troponins is going to be the best way to
go. I'm a little bit skeptical about troponin-only approaches.


Dr Deb
Diercks:                
That's a great summary. I don't think it's time to throw out all
the value of that risk stratification tool, and I think your
study showed that how it can easily be incorporated into what we
do in a manner that doesn't really negatively impact the work
flow, which I think is so important.


Dr Simon
Mahler:            
You know, we did a smaller study where we looked at the
performance of the HEART Pathway with high-sensitivity assays. We
studied it with both the Roche troponin high-sensitivity troponin
T and the Abbott high-sensitivity I, and at the 99th percentile
it actually made very little difference in terms of the
performance of the HEART Pathway. What the potential advantages
of incorporating high-sensitivity assays is that you probably no
longer need a 0 and 3 hours, evaluation can be condensed. I think
there's a lot of really interesting questions that availability
of high-sensitivity troponins has created, and I think that
there's gonna be a lot of emerging evidence over the next few
years about new Pathways, and what are the best ways to fully
take advantage of these higher-sensitive assays because, frankly,
most of the decision aids that are currently in use they were
developed using contemporary troponins, and they may not fully
take advantage of high-sensitivity troponins. We may see
modifications of our Pathway, and it will interesting to see kind
of how things evolve as we study the impact of high-sensitivity
troponin.


Dr Carolyn
Lam:               
Wow, exciting work ahead. Just one last question regarding the
future. So, you followed up the patients in your study for 30
days. Am I wrong? Any plans to follow them up longer, and do you
think such data are needed?


Dr Simon
Mahler:            
Yeah, we actually followed them for a year. Our primary analysis
was through 30 days, and so we do have one-year data on all of
our patients, and so we'll be doing a secondary analysis looking
out to a year. Yeah, you can look forward to that coming up
hopefully in the next six months or so.


Dr Carolyn
Lam:               
That is awesome. Thank you so much, Simon. Thank you so much,
Deb. Thank you, listeners, for joining us today. You've been
listening to Circulation on the Run. Don't forget to tune in
again next week. This program is copyright American Heart
Association 2018.