Circulation October 17, 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.


                                               
Our feature discussion this week centers on the temporal changes
in natriuretic peptides preceding heart failure hospitalizations
and patients at high risk. Data that are really novel and have
implications for the way we perhaps monitor and categorize these
high risk patients. Well, more soon right after these summaries.


                                               
The first original paper this week provides the first
epigenome-wide association study in patients with heart failure.
Now, epigenetics refers to biochemical DNA modification such as
methylation of gene bodies, and post-translational modification
of histones, which is increasingly recognized to play a crucial,
regulatory interface between genes, environment, and the
transcriptome.


                                               
The lack of availability of myocardial specimens from patients
has been a major roadblock for elucidating the impact of such
epigenetic changes on complex cardiovascular traits. However, in
today's paper from first author, Dr. Meder, corresponding author,
Dr. Katiz and colleagues from University of Heidelberg, Germany.
The authors performed the first multi-omic study in myocardial
tissue and blood of patients with dilated cardiomyopathy compared
to controls.


                                               
They detected 59 epigenetic loci that are significantly
associated with dilated cardiomyopathy, with three of them
reaching epigenome-wide significance. 29 of these loci could be
replicated in independent cohorts and authors further linked a
subset of 517 epigenetic loci with dilated cardiomyopathy and
cardiac gene expression.


                                               
Finally, they identified distinct epigenetic methylation patterns
that are conserved across tissues. Thus representing novel,
epigenetic biomarkers for heart failure.


                                               
The next study is the first to assess a diagnostic and prognostic
value of cardiac myosin binding protein-C in patients presented
with possible acute myocardial infarction or AMI. Cardiac myosin
binding protein-C is a cardiac restricted protein that is more
abundant than the cardiac troponins and is released more rapidly
following AMI.


                                               
In today's paper, first author, Dr. Kaya, corresponding author,
Dr. Marber and colleagues from the Rayne Institute In St.
Thomas's hospital in London evaluated cardiac myosin binding
protein-C as an adjunct or alternative to cardiac troponins in
the early diagnosis of AMI in 1,954 unselected patients
presenting to the emergency department with symptoms suggestive
of AMI.


                                               
The final diagnosis of AMI was independently adjudicated in 340
patients. The authors found that concentrations of cardiac myosin
binding protein-C at presentation were significantly higher in
those with versus without an AMI. The discriminatory power for
AMI quantified by the area under receiver operating curve was
comparable for cardiac myosin binding protein-C to high
sensitivity cardiac troponins T and I, and even superior to
standard sensitivity cardiac troponin I. The use of cardiac
myosin binding protein-C more accurately classified patients with
a single blood test and to rule out or rule in categories in
early presenters, meaning those with chest pain of less than
three hours.


                                               
The improvement in rule in or rule out classification with
cardiac myosin binding protein-C was larger compared with higher
sensitivity cardiac troponins T and I. Finally, cardiac myosin
binding protein-C was superior to high sensitivity and standard
troponin I and similar to high sensitivity cardiac troponin T at
predicting death at three years. Thus in summary, this paper
shows that cardiac myosin binding protein-C at presentation
provides discriminatory power comparable to high sensitivity
troponins T and I in the diagnosis of AMI and may perform
favorably in patients presenting early after symptom onset.


                                               
The next paper describes the discovery of a novel candidate
cardiomyopathy or arrhythmia gene. First author, Dr. Barryfield,
corresponding author Dr. McNally from Center of Genetic Medicine
in Chicago and colleagues studied a family with dilated
cardiomyopathy and associated conducted system disease in whom
prior clinical cardiac gene panel testing was unrevealing. Whole
genome sequencing however, identified a premature stop codon in
the gene encoding a novel myo filament component, the myosin
binding protein-H-like.


                                               
Having identified this gene, they turned to experimental
approaches. The myosin binding protein-H-like gene was found to
have high atrial expression with low ventricular expression. The
truncated protein failed to incorporate into the myo filament.
Human cell modeling demonstrated reduced expression of the mutant
allele. Heterozygotes and nullumites exhibited a reduction in
fractional shortening and increased diastolic ventricular chamber
size, aberrant atrio-ventricular conduction and an increased rate
of arrhythmia associated with the expression of the myosin
binding protein-H-like in the atria, as well as in discrete
puncta throughout the right ventricular wall and septum.


                                               
These findings therefore support that myosin binding
protein-H-like truncations may increase the risk for human
arrhythmias and cardiomyopathy.


                                               
Transplantation of cells into the infarctant heart has
significant potential to improve myocardial recovery. However,
low efficacy of cell engraftments still limits the therapeutic
benefit. In today's paper, authors describe a method for the
unbiased, in-vivo selection of cytokines that may improve
Mesenchymal stromal cell engraftment into the heart. In this
paper from first author, Dr. Bortolotti, corresponding author Dr.
Giacca, and colleagues from University of Trieste in Italy, an
arrayed library of 80 secreted factors were individually cloned
into adeno-associated viral vectors.


                                               
Pools from this library were then used for the batch transduction
of bone marrow derived Mesenchymal stromal cells ex-vivo,
followed by intra myocardial cell administration in normal and
infarctant mice. Three weeks after injection, the vector genomes
were recovered from the few persisting cells, and identified by
sequencing DNA barcodes that were uniquely labeled for each of
the tested cytokines.


                                               
Using this novel, competitive, engraftment screening methodology,
the authors identified that the most effective molecule was
cardiotrophin-1 a member of the IL-6 family. Intra cardiac
injection of Mesenchymal stromal cells preconditioned with
cardiotrophin-1 preserved cardiac function and reduced infarct
size parallel to the persistence of the transplanted cells in the
healing hearts for at least two months after injection. Thus,
preconditioning with cardiotrophin-1 might represent an efficient
manner to improve the currently poor cell retention in patients
treated with Mesenchymal stromal cell therapy.


                                               
The final paper presents results of the early myo trial, a
non-inferiority trial comparing a pharmacoinvasive strategy with
half-dose alteplase versus primary PCI in patients with STEMI,
presenting six hours or less after symptom onset but with an
unexpected PCI related delay.


                                               
First author, Dr. Poole, corresponding author, Dr. Hua and
colleagues from Shanghai Jiao Tong University in China randomized
a total of 344 patients from seven centers to a pharmacoinvasive
arm or a primary PCI arm. They found that pharmacoinvasive
strategy was non-inferior to primary PCI for the primary endpoint
of complete epicardial and myocardial reperfusion after PCI
defined as TIMI flow grade 3, TIMI myocardial profusion grade 3,
and ST-segment resolution of more than 70%.


                                               
There was no significant differences in the frequency of the
individual components of the combined endpoint. Infarct size and
left ventricular ejection fraction were similar in both groups
and there was no significant differences in 30-day rates of total
death, re-infarction, heart failure, major bleeding events, or
intracranial hemorrhage. However, minor bleeding was observed
more often in the pharmacoinvasive group.


                                               
Thus the authors concluded that a pharmacoinvasive approach with
reduced dose alteplase seems to offer effective and safe
reperfusion in low-risk patients with STEMI with an unexpected
PCI related delay. Further large, randomized control trials
powered for clinical endpoints are needed.


                                               
Well, that wraps it up for your summaries. Now for our feature
discussion.


                                               
The measurement of natriuretic peptides BNP, NT-proNP have
certainly become the cornerstone of heart failure management. We
measure these levels by guidelines in patients who are presenting
with symptoms and suspected heart failure, in patients who are
hospitalized. We measure them for prognostication purposes at
discharge. However, what we don't really know is how the
preceding changes in natriuretic peptides may precede heart
failure hospitalization in patients who are at high risk of
developing heart failure.


                                               
For example, patients with a recent coronary event or type-2
diabetes. And this is the very subject of our feature paper
today, and I am so pleased to have the corresponding author of
today's paper which is really a research letter. Dr. Brian
Claggett from Brigham and Women's Hospital as well as Dr. Biykem
Bozkurt who's our senior editor from Baylor College of Medicine.


                                               
Welcome both, and maybe I could start, Biykem could you let us
know, what are the unanswered questions in heart failure relating
to natriuretic peptides and how do you see this paper falling in,
clinically?


Dr. Biykem Bozkurt:       
Carolyn, this is a wonderful I think prelude to perhaps
preventing heart failure events. And as you are aware, we in the
recent year changed our guidelines at the ACC, AHA, and the HFSA
incorporating screening high risk patients for development of
incident heart failure. And the study that resulted in this
consideration was a STOP-HF trial which was utilizing natriuretic
peptides in high risk patients to determine whether their closer
follow up in a multidisciplinary fashion would result in earlier
detection and prevention of heart failure, and which it did.


                                               
And this study I think is straddling the concept of high risk or
stage A or B patients because they are individuals who have had
heart attacks, coronary events, and they have type-2 diabetes so
they are definitely high risk. And doing natriuretic peptides as
an outpatient, whether that would predict the heart failure
hospitalizations.


                                               
And in essence I think it's a good concept. Perhaps the
challenging concepts are how often should we screen our patients,
and what will be the threshold of the rise that would potentially
make us act in either earlier diagnostic strategies, or
management strategies. I think those are the two unanswered
questions that remains.


                                               
How are we gonna screen our patients? Our high risk patients to
determine when they are developing heart failure before they
become symptomatic? So, what threshold are we going to use?


Dr. Carolyn
Lam:              
That is a perfect set up. I just wanted to add as well in
addition to STOP-HF there was the PONTIAC study in diabetics
which is very relevant to today's paper that also sort of used
NT-proBNP to risk stratify patients for prevention of heart
failure. But neither of these studies talked about the temporal
changes in natriuretic peptides. And I think a lot of the reason
for that is, is that the methods, I mean the statistical methods
to do that sort of thing are mind-blowing.


                                               
And so Brian, could you now please share with us what you did,
the methodology and basically what you found before we discuss
the two questions that Biykem brought up?


Dr. Brian
Claggett:          
What was really interesting is the method that we came up with to
look at these questions. It's something that we like to believe
will be generalizable and can be used in other scenarios and for
other biomarkers. But the idea that we have is that we are always
used to thinking about the design of a clinical trial as being
very regimented. So, you see a patient once at baseline, and then
maybe six months later, and then maybe six months after that, and
so on. And so it's hard to know what's going on, on a day to day
or week to week basis.


                                               
But if you think backwards, and you think backwards from the time
of any sort of event, because those events whether they're
hospitalizations or MIs or death, they happen not on that same
schedule. And so odds are at the end of a trial, you had a
patient who came to a scheduled visit and then had an event the
next day. And you probably had a patient who came in for a visit
two days before an event, and another patient who came in a week
before an event. So if you start thinking on that time scale, you
can piece together all these different time frames when you do
have data collected and try to reconstruct something that looks
like an actual continuous natural history of what that biomarker
would have looked like over say a two year period, if it had been
measured continuously.


Dr. Carolyn
Lam:              
So, tell us what you found. First of all, let's just make sure
that everyone knows you were looking at the ELIXA cohort, right?


Dr. Brian
Claggett:          
Yes, the data that we had available for this analysis comes from
the ELIXA trials, it was 6,068 patients all with type-2 diabetes
and a recent ACS event. Recent meaning within the last 180 days.
And they were randomized placebo versus a diabetes drug,
lixisenatide. And they were followed up for cardiac outcomes.


                                               
Beyond that, the natriuretic peptides were measure systematically
at baseline, month 6, month 18, and month 24 in all patients who
were participating in the trial. So this was the richest
collection of a large number of patients being measured multiple
times, systematically and not in just a sub-sample of the
population. So, we felt like this was a great opportunity to
learn something about what happens. What can you learn when you
measure these natriuretic peptides over and over again.


                                               
And even more interesting than that, the fact that this wasn't a
heart failure trial meant that some of the patients already had
heart failure at baseline. Other patients didn't have heart
failure, but as the trial went on, they developed or were
hospitalized for heart failure for the first time. And so we were
able to also look at differences between patients experiencing
their first heart failure, versus those with more long standing
disease.


Dr. Carolyn
Lam:              
And that was very, very unique methodology that you spoke about.
And I fully agree that it's going to be used more. I am staring
at your beautiful figure one right now. That really, really says
it all. Could you walk us through the results?


Dr. Brian
Claggett:          
Sure, I think our key finding is that, I guess no matter when you
measure patients. Patients with a higher level of NT-proBNP, or a
higher level of BNP at any given time are going to be at higher
risk of developing heart failure in the future.


                                               
But as we start looking at this as a temporal process, what we
see is that there seem to be a noticeable acceleration in these
increases, specifically in the last six months before development
of heart failure. Or, before a hospitalization for heart failure.
And that increase in the final six months seems to occur both in
patients who had no prior history of heart failure and also in
patients with a history of heart failure. So that six month
window I think is something that we learned that we didn't
necessarily know before.


Dr. Carolyn
Lam:              
But, going back to Biykem's questions, do you think we have
answers to how often we need to survey natriuretic peptides in
these high risk patients and what threshold we need to act on?


Dr. Brian
Claggett:          
I think both are very important. I think maybe the timing and the
thresholds are somewhat separate questions. I think we're better
able to answer the timing question. At the very least we can say
that if dramatic changes are happening over a six month window
that measuring patients only once every six months probably isn't
enough. Whether that means it needs to be every three months, or
two months, or one month, or something more than that, I think
it's hard to know exactly what the right answer is. But I think
we are confident in saying that things happen relatively quickly
and we need to be measuring these things more frequently.


                                               
As far as the question of thresholds, I think that's maybe even a
more difficult question. Or even the idea of a threshold means
that we think that there's some magic number and I am not sure
that we know for sure what's more important, the absolute number
or is it the ... if someone starts relatively low and that
relatively low number doubles over the course of six months. That
might still be prognostically just as important as someone who's
been consistently edging just below or just about that threshold
level.


                                               
I'm not sure that we're confident enough to say that the changes,
the speed of the changes, or the relative changes, or some
absolute threshold is the most important thing to be paying
attention to. But, I think where these two are related is the
more ... that we can start to collect this data more frequently
and be able to analyze it. I think that gives us a lot better
chance of being able to successfully answer that question about
thresholds.


Dr. Carolyn
Lam:              
Indeed. Stuff for future work, huh? Biykem, what do you think?


Dr. Biykem Bozkurt:        I
wanted to point out two things from Brian's study which was quite
interesting. One is the trajectory of the rise, or the delta
changes in the natriuretic peptides was quite different in the
patients with no history of heart failure compared to those with
a history of heart failure. The trajectory, or the linear rise,
or the delta changes were more prominent in the individuals with
no history of heart failure. Probably intuitively expected so
because their baseline levels are not as high as the individuals
with history of heart failure.


                                               
So, it almost gives the impression that maybe in low low risk,
the screening or the frequency may need to be lower, and if low,
then probably the likelihood of the rise may be less. But those
individuals who, as you said, are edging upward, then maybe the
frequency may need to be higher and there may be perhaps a linear
rise or a more prominent rise about six months before the
incident event.


                                               
So, it's an interesting concept just to look at people's
trajectories. But, as you said, probably individualization and
monitoring or targeting may need to be individualized according
to personal risk and other features. And one then wonders
futuristically if this would be a concept that would be point of
care testing maybe done by the patients similar to glucose
monitoring. And in the event that we were to be able to carry the
platform to self-test.


Dr. Brian
Claggett:          
You're talking to a statistician, so I am always going to be in
favor of collecting more data all the time. So I agree with that.


Dr. Carolyn
Lam:              
Wow, what an insightful discussion. Thank you both for joining us
on this podcast today.


                                               
Ladies and gentlemen out there, you heard it right here in
Circulation on the Run. Tune in again next week.