Circulation November 7, 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.


                                               
In just a moment, we will take a deep dive into the issue of age
and its association with outcomes of primary prevention ICDs in
patients with non-ischemic systolic heart failure.


                                               
Yes, a long-awaited discussion from the Danish trial. That, in
just a moment. First, here's your summary of this week's Journal.


                                               
The first original paper provides evidence of a true association
between disturbed genetic imprinting and Preeclampsia. This paper
is from co-first authors, Dr. Zadora, and Dr. Singh, and
co-corresponding authors, Dr. Izsvak, from the Max Delbrück
Center for Molecular Medicine; Dr. Hurst, from the University of
Bath; and Dr. Dechend, from the Experimental and Clinical
Research Center of Berlin.


                                               
These authors performed an unbiased analysis of genome-wide
molecular data on raw characterized patient material, from normal
controls, and patients with  Preeclampsia, and identified
DLX-5 as an imprinted target gene, with novel placental function
in Preeclampsia. Due to loss of imprinting, DLX5 was upregulated
in 69% of placentas from Preeclampsia patients. Levels of DLX5
correlated with the classical Preeclampsia markers.


                                               
DLX5 was expressed in human, but not in urine trophoblast,
underlying the known human specificity of Preeclampsia. Finally,
DLX5-induced overexpression if trophoblasts faithfully modeled
Preeclampsia in a cell culture system. In summary, this paper
shows that disturbed imprinting is common, and may play a causal
role in Preeclampsia.


                                               
The next study affirms that stenosis severity is better
discriminated using coronary invasive physiologic indices, than
using coronary angiographic assessment. First author, Dr. Lee,
corresponding author Dr. Koo, colleagues of Seoul National
University Hospital, studied 115 patients with left anterior
descending artery stenosis, who underwent both ammonia positron
emission tomography, or PET, an invasive physiologic measurement.


                                               
Myocardial blood flow measured using PET, and invasively measured
coronary pressures, were used to calculate microvascular
resistance, and stenosis resistance. They found that both
fractional flow reserve, or FFR, and instantaneous weight free
ratio, or IFR, decreased as angiographic stenosis severity,
resistance, and pressure gradient increased, and hyperemic
myocardial blood flow decreased.


                                               
When the presence of myocardial ischemia was defined by both low
hyperemic myocardial blood flow, and low coronary flow reserve,
the diagnostic accuracy of FFR and IFR did not differ, regardless
of cutoff values for hyperemic myocardial blood flow, and CFR.
However, at any given stratum of a given stenosis, physiologic
classification of stenosis severity using FFR or IFR showed
better discrimination of a unique relationship between absolute
myocardial blood flow, and pressure gradient, than anatomic
classification using angiographic percentage.


                                               
In summary, by demonstrating coronary physiologic responses to
coronary stenosis, these authors showed that stenosis severity is
better discriminated, using invasive physiologic indices, than
using angiographic assessment.


                                               
The next paper identifies a previously unknown angiogenic growth
factor that can be enhanced therapeutically to repair the heart
after myocardial infarction. This novel growth factor is
endoplasmic reticulum membrane complex, Subunit 10, or EMC10,
which the authors previously identified by bioinformatic
secretome analysis in bone marrow cells.


                                               
In the current paper, from co-first authors Dr. [Rabel 00:04:35],
and [Krof Clengobill 00:04:37], and corresponding author Dr.
Wollert, from Hanover Medical Center, and colleagues, the authors
investigated the angiogenic potential of EMC10, and its mouse
homologue, in cultured endo fetal cells and infarcted heart
explants. They found that EMC10 and its mouse homologue signal a
virus, small GTAPases; p21-activated kinase; and p38
mitogen-activated protein kinase, to promote endothelial cell
migration.


                                               
In mice with acute myocardial infarction, bone marrow derived
monocytes and macrophages produced EMC10 endogenously, to enhance
infarct vascularization, tissue repair, and heart function.
Furthermore, subcutaneous treatment with recombinant EMC10 for
one week, after myocardial infarction, augmented infarct
vascularization and repair, and led to a sustained improvement in
heart function and survival.


                                               
The next study is the first prospective randomized trial of
screening for atrial fibrillation, with a smartphone-based,
single-lead, electrocardiographic system in 1,001 patients, aged
65 years and above, with a CHA2DS2-VASc score of two and above,
and without a history of atrial fibrillation.


                                               
In this paper, from first and corresponding author Dr. Halcox,
from Swansea University Medical School, in the United Kingdom,
and colleagues, patients were randomized, either to biweekly
electrocardiographic recordings with the iPhone device, or to
routine over a 12-month period.


                                               
The smartphone-based electrocardiographic approach was at least
three times more likely to identify incident atrial fibrillation,
than routine care, and at a cost of just over $10,000 per case
identified, and was judged to be a highly acceptable approach in
this group of patients. These results support consideration of
evaluation in an appropriately-powered, event-driven randomized
trial, to confirm the clinical and cost effectiveness of such an
approach to stroke prevention in atrial fibrillation.


                                               
Well, that wraps it up for your summaries. Now for our feature
discussion. The Danish trial really created a huge splash last
year, when it was reported that a primary prevention ICD in
patients with non-ischemic systolic heart failure, may not
actually reduce all cause mortality. Something that we had,
perhaps, taken for granted, and in fact, entered our guidelines.


                                               
Now, however, there was a pre-specified subgroup analysis at the
time, that suggested a possible age-dependent association,
between ICD and mortality, in the Danish trial. This week, we are
so pleased to be discussing an in-depth analysis of the
association between age and outcomes in the Danish trial.


                                               
I'm so pleased to have the first author of today's featured
paper, Dr. Marie Bayer Elming, of Copenhagen, Denmark, as well as
Dr. Sana Al-Khatib, who's not only an associate editor of
circulation, but also the author of an accompanying, and she is
from Duke, Durham, North Carolina. Welcome, ladies!


Dr. Bayer
Elming:             
Thank you. Happy to be here.


Dr. Sana
Al-Khatib:         
Thank you so much.


Dr. Carolyn
Lam:              
Sana, could you start by framing why this paper is so important,
and why we've been looking forward in anticipation to these
results?


Dr. Sana
Al-Khatib:         
Absolutely. As you know, data on the outcomes of primary
prevention ICDs in patients with non-ischemic cardiomyopathy
started emerging in the early 2000s, or so. Then in 2005, the
sudden cardiac deaths and heart failure trial was published, that
included a large number of patients with non-ischemic
cardiomyopathy, and absolutely showed survival benefits from
primary prevention ICDs in those patients. Of course, there were
also patients with ischemic cardiomyopathy.


                                               
But really, that trial formed the basis of the guidelines,
recommendations, that have informed our practice for the last 12
years, that basically tell us that we should consider implanting
a primary prevention ICD in patients with non-ischemic
cardiomyopathy, who have an EF of 35% or less, who have Class II
or III heart failure symptoms. As long as they are on optimal
care at the end, they have a reasonable life expectancy.


                                               
So that's what's we've been doing for years, and then, the Danish
trial was published this past year, that really called into
question the prior findings, and the current practice. Because
Danish, as you stated, showed no survival benefit with primary
prevention ICDs, but there are many aspects about the trial that
people need to pay attention to, to put the results in
perspective.


                                               
The fact that 58% of patients in the trial, in those arms,
received cardiac resynchronization therapy ... the fact that the
trial required that patients have an elevated NTproBMB level, to
be considered for enrollment ... that may have biased the results
toward a higher risk of non-sudden cardiac deaths, so on, so
forth.


                                               
I think what was really interesting, and caught people's
attention, when the paper was published, was this subgroup
analysis that showed that younger patients may benefit more than
older patients. I think, many of us, Carolyn, were really
awaiting the results of a more dedicated analysis, looking at age
in Danish, and Dr. Elming and her colleagues did a great job
looking at this very closely in their paper, and showed great
results, and probably will let Dr. Elming share those results
with us.


Dr. Carolyn
Lam:              
Yes, absolutely, Sana. Actually, I just wanted to echo how
surprised everyone was, and the immediate thing was, "Oh, my
goodness. What do we do with the guidelines?" Maybe we should get
back to that later, and Marie, please share with us, what did you
do, and what did you find this time?


Dr. Bayer
Elming:             
The reason why we did this study was that, in this main Danish
trial, age was the only one of the 13 pre-specified subgroups
that had a significant treatment by a subgroup interaction. This
suggested that a younger patient might have a survival benefit
from ICD ... the implication, even though the overall study was
neutral. So we wanted to further investigate this relationship
between age and effective ICD implantation.


                                               
What we did was to look at the relation between age and effective
ICD, and we found that there was this linear relation, for each
year of younger age, that was associated with a reduction, a 3%
reduction in the hazard ratio, for the benefit of ICD.


                                               
Also, we did this selection impact curve, which is a bit
technical, but what it does is to describe the expected survival
for the population, on as a whole, for the different age cutoffs
for ICD treatments.


                                               
So, if we take into account, both the patients receiving an ICD,
and those who did not, we could see why we would get the highest
survival for the population as a whole. What we found was that,
when no one in the population received an ICD, around 70% would
survive.


                                               
If everyone in the population received an ICD, only 72% would
survive, but if we chose 70 years as the age cutoff ... so,
patients younger than 70 years received an ICD, and patients
older than 70 years did not receive an ICD, we got the highest
survival for the population, and 75% would survive.


Dr. Carolyn
Lam:              
Thank you, Marie. What important results. So, maybe, still
consider ICDs for primary prevention ... in our non-ischemic
systolic heart failure, patients were less than 70 years old. Is
it as simple as that, Sana? You wrote a beautiful editorial. Tell
us, what are the clinical implications?


Dr. Sana
Al-Khatib:         
This is an important question. Danish was an important trial, but
in my mind, it truly doesn't refute the role of primary
prevention ICDs in patients with non-ischemic cardiomyopathy. As
I mentioned earlier, the majority of patients enrolled in Danish
received a CRT device. And so, you end up questioning, what does
that actually mean, for those patients who are not eligible for
cardiac resynchronization therapy?


                                               
So, I actually believed that, and as you know, Carolyn, and maybe
Marie knows, as well, there have been several meta analyses that
have been published, combining data on patients with non-ischemic
cardiomyopathy only, and excluding patients with cardiac
resynchronization therapy from Danish, that have actually now
shown, consistently, a significant improvement in survival, with
a primary prevention ICD ... including one that was done by our
group.


                                               
So, no, I don't think that, based on the results, we should say,
"No, we shouldn't be offering primary prevention ICDs to patients
with non-ischemic cardiomyopathy," and this beautiful analysis
that was done by Marie and her group actually shows that, at
least for those patients who are 70 years of age and younger, I
think we should absolutely continue to consider them for the
therapy, and offer them the therapy, if they're appropriate
candidates.


                                               
Then, of course, if the patients are older than 70,, and they
meet criteria for cardiac resynchronization therapy, I think it
will be important for us to be talking to the patients about ...
is the RTD with a defibrillator, versus a CRTP only, with a
pacemaker, and talking about the pros and cons, and everything
else? But in those patients who are older than 70, who don't meet
criteria for CRT, I think more research is needed, to really
understand the role of primary prevention ICDs in those patients.
We definitely need more data there.


Dr. Bayer
Elming:             
I definitely agree that, of course, for the patients older than
70 years were not candidates for CRT treatment. These patients,
we do not know very much about 'em, and this study that we did,
do not answer that question. Based on the Danish study, and this
further analysis of the age inspection, the guidelines in Denmark
also state that patients younger than, we say, 68 years, because
that was the age cutoff used in the '08 Danish trial, you should
definitely think of giving patients with non-ischemic
cardiomyopathy an ICD.


                                               
But for the older patients, it depends on a variety of
co-factors, such as co-morbidity, or frailty, and it should be an
individual assessment of the patient. So, I agree with you, Sana.


Dr. Carolyn
Lam:              
That's wonderful. Hey, just one more question. Sana, I'd like you
to put on your AE hat, now, and sort of think with me. In
circulation, we don't ... well, we're careful about publishing
subgroup analyses, so to speak, right, of results. You
articulated, in your editorial, reasons why this, perhaps
subgroup analysis, may be different from others. Could you
elaborate on that a bit?


Dr. Bayer
Elming:             
Yeah, and absolutely, that's a great question. As you pointed
out, I mean, you really ... the conventional wisdom in clinical
research is to be careful, interpreting subgroup analyses. I
think there are some strengths in this particular analysis, as
Marie stated: "Here's what we specified." The other thing is, I
believe that Marie and her group then came, and did their very
robust statistical methods, and really, probably most
importantly, if you look at their findings, they actually really
align well, and support their main conclusion.


                                               
For example, looking at the fact that older patients had the
higher presence of co-morbidities, that they had a higher level
of [Co-BMP 00:17:00], they had had a longer duration of heart
failure ... I mean, all those things most likely had an impact on
their mode of death, really making it more likely for those
patients to succumb to non-sudden cardiac death. I think the
whole story makes a lot of sense.


Dr. Bayer
Elming:             
If I can elaborate a bit on this, I think one of the important
findings from the study is that we show that mode of death varied
according to age. So, the rates of sudden cardiac death were
almost similar, between the younger and the older part of the
population. But the rates of non-sudden death were almost twice
as high in the older part of the population. This is a really
good explanation why the ICD implantations have less impact in
the older patients.


Dr. Carolyn
Lam:              
Yeah, because ICDs would definitely not be expected to reduce
non-sudden cardiac deaths. Really, really, well put. Oh, thank
you so much, Marie. We're so proud to be publishing your
beautiful paper, as well as your editorial, Sana, and thank you
for this great conversation.


                                               
Well, listeners, I'm sure you enjoyed that as much as I did.
Thank you for joining us this week, and don't forget to tune in
next week.