Circulation August 8, 2017 Issue

Carolyn:              
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.


                               
Later on in this podcast, we will be meeting Dr. Nancy
Schweitzer, Editor-in-Chief of the new Circulation Heart Failure.
We will be discussing today's feature paper on acute myocarditis
as well as hearing about her visions for the journal. All that
coming right up after these summaries.


                               
The first original paper this week suggests that day-to-day blood
pressure variability may be a significant risk factor for
dementia. First author Dr. Oishi, corresponding author Dr. Ohara,
and colleagues of Kyushu University from Fukuoka, Japan, studied
a total of 1,674 community-dwelling Japanese elderly without
dementia, who were followed up for five years, and had home blood
pressure measured three times every morning for a median of 28
days.


                               
They found that the age and sex adjusted incidences of all-cause
dementia, vascular dementia, and Alzheimer's disease increased
significantly with increasing day-to-day variability of home
systolic blood pressure. These associations remained unchanged
after adjusting for potential confounding factors, including
average home systolic blood pressure. The study, therefore,
suggests that the measurement of day-to-day blood pressure
variability, using home blood pressure monitoring, may be a
useful way to assess future risk of dementia, irrespective of
dementia subtype.


                               
The next paper is one of the first studies to directly target a
gene within the fibroblast of a mammalian heart and show a direct
role in regulating cardiac fibrosis. Co-corresponding authors Dr.
Molkentin from Howard Hughes Medical Center and Cincinnati
Children's Hospital Medical Center and Dr. Davis from University
of Washington and colleagues performed an elegant series of mouse
experiments to show that the gene-encoding p38 alpha
mitogen-activated protein kinase was required to mediate
fibroblast activation in the mouse heart following injury.


                               
They also showed that forced activation of p38 within
fibroblasts, using a transgenic approach, was sufficient to drive
fibrosis in multiple tissues of the mouse, including the heart.


                               
In totality, their findings indicated that p38 mitogen-activated
protein kinase was a nodal signaling effector within the cardiac
fibroblast that drove both wound healing and long term fibrosis
in heart failure. In other words, it appears to play a crucial
role in the control of both physiological and pathological
processes. The clinical implications are that pharmacologic
inhibition of p38 mitogen-activated protein kinase in heart
failure could reduce progressive fibrosis. However, the same
inhibition during acute myocardial infarction injury may inhibit
wound healing and be detrimental. These issues are discussed in
an accompanying editorial by doctors, Stratton, Koch and
McKinsey.


                               
Receptors, well known for their roles in angiogenesis and cancer,
may play a role in atherosclerosis, as shown in the next paper,
which looked at the Eph-family of receptor tyrosine kinases.
These are the largest family in the mammalian genome, which
interact with ephrin ligands on adjacent cells to mediate cell
adhesion repulsion signaling.


                               
First author, Dr. Finney, corresponding author, Dr. Orr, from LSU
Health Sciences Center, Shreveport, and colleagues assessed the
role of EPHA2 in atherosclerosis by deleting the EPHA2 in a mouse
model of atherosclerosis and by assessing EPHA2 function in
multiple vascular cell culture models.


                               
The authors identified a novel role for EPHA2 in atherosclerosis
by regulating both plaque inflammation and progression to advance
atherosclerotic lesions. Cell culture studies suggested that
endothelial EPHA2 contributed to atherosclerotic inflammation by
promoting monocyte firm adhesion, whereas, smooth muscle EPHA2
expression regulated the progression to advanced atherosclerosis
by regulating smooth muscle proliferation and extracellular
matrix deposition.


                               
The clinical implications are that blunting EPHA2 ligation may
selectively reduce plaque-associated inflammation. Since the
effect of EPHA2 on smooth muscle proliferation appears to be
largely ligand independent, unlike its effect on inflammation,
the blunting of EPHA2 ligation may limit inflammation while
leaving smooth muscle fibroproliferative remodeling intact.


                               
Well, that wraps it up for our summaries. Now, let's go to our
feature discussion.


                               
Our feature paper today may cause us to think a little bit
differently about fulminant versus non-fulminant acute
myocarditis because the findings are actually in contrast with
previous studies and are extremely insightful.


                               
And, to discuss this, I am so pleased to have the corresponding
author, Dr. Enrico Ammirati from Niguarda Hospital in Milan,
Italy, as well as Dr. Nancy Sweitzer, Associate Editor of
Circulation from University of Arizona, who managed this paper.
But importantly, also, the Editor In Chief of Circulation Heart
Failure. Welcome, Enrico and Nancy.


Enrico:                 
Hello.


Nancy:                 
Thank you, Carolyn.


Carolyn:              
Enrico, could I ask you to start by clarifying the conditions
that we're talking about here? When we say acute myocarditis or
fulminant myocarditis, and non-fulminant myocarditis, what
exactly are we referring to?


Enrico:                 
We refer to an acute condition and fulminant myocarditis is a
myocarditis inflammation of the myocardium that's a media
anatomic or mechanical support due to an anatomic instability,
while non-fulminant myocarditis it's a condition where the
patient remains hemodynamically stable. Previous records have
suggested that despite their dramatic presentation of patient
with a fulminant myocarditis might have better outcome than those
with acute fulminant myocarditis.


                               
Now in this study we have over 55 patients with fulminant
myocarditis and in particular, 34 patients with fulminant
myocarditis with viral genomes within two weeks from the onset of
symptoms, whereas in the previous record, in particular from
[inaudible 00:07:38] we have shown in 15 occasions of fulminant
myocarditis, that fulminant myocarditis as quite a good
prognosis.


                               
But what we believe it is that gives disparity between our
results that connected all acute patients admitted to the
emergency department with [inaudible 00:08:01] and symptoms onset
within one month to two weeks before. Is the main difference
comparing [inaudible 00:08:11] this study [inaudible 00:08:13]
patient with onset of symptoms since one year before the onset of
symptoms. And we believe that we enroll acute patients.


                               
Whereas in the other study, there was sort of selection by us. It
was true that in those previous studies, they have all just
patients who we were endomyocardia biopsied performed whereas in
our study we did not perform endomyocardia biopsies in that case.
But we feel that we have a snapshot of the acute stage of a
fulminant myocarditis, so we connected all the patients, whereas
in previous study, maybe some of the patients they had acute
symptoms died before evaluation from the other researchers.


Carolyn:              
Indeed, it makes a lot of sense that there may be some survival
bias involved. For example, if the sickest patient didn't get a
biopsy, for example.


                               
Nancy, when you were managing this paper, what were the kind of
the discussions that occurred at the editorial discussions?


Nancy:                 
I think that Dr. Ammirati pointed it out really well. The editors
felt that this was a very important paper because it really
looked inclusively at myocarditis in the modern era, and showed
us where perhaps bias in prior studies had led us astray in terms
of our beliefs about, particularly the outcomes in this syndrome.
Not only the outcomes in the fulminant patients, who have a very
profound and important early mortality risk, but also the
outcomes in the non-fulminant patients, who in this study, really
do extremely well and do not progress to LV dysfunction, which
has been a long-held belief, I think. So understanding much
better the full spectrum of myocarditis was made much easier
because of the comprehensive look Dr. Ammirati and his colleagues
took.


Carolyn:              
Enrico, I do congratulate you on a beautiful paper. As I said, as
a heart failure cardiologist myself, it has changed my thinking.
Could you maybe share just a bit more details of what your study
found and how this is important clinically?


Enrico:                 
What we have found it is that hospital deaths or heart
transplantation was about 25 percent in fulminant myocarditis
compared to ten percent in non-fulminant myocarditis and despite
greater improvement in the left ventricle injection fraction
[inaudible 00:10:56] in fulminant myocarditis compared to
non-fulminant forms. The proportion of patients with the left
ventricle injection fraction below 55% [inaudible 00:11:09] was
higher in fulminant myocarditis comparing it to non-fulminant
myocarditis. So we have to pay great attention to do this form of
myocarditis not thinking that this is a condition that can simply
recover with time but we have to aggressively manage this
condition, and we have to see about trials designed [inaudible
00:11:39] in this specific setting to improve the [inaudible
00:11:50] outcome and to reduce myocardial injury during the
acute phase.


Carolyn:              
True. And Nancy, I mean you see tons of these patients too. How
has this impacted you?


Nancy:                 
It's interesting, it definitely has impacted me. I like everyone,
taught and taught on my teaching rounds for many years that the
fulminant patients we were seeing, despite how ill they were,
would have better outcomes than those who were non-fulminant. And
also, many patients who present with dilated cardiomyopathy who
are non-ischemic are told after searching for some viral illness
in the year prior to their presentation that probably they had a
virus attack the heart or an inflammation of the heart. I've
stopped saying those things, and I continue to see review of
papers that I'm handling about myocarditis refer to these
misconceptions. So I think this is going to be a really important
paper, and clarifying our understanding of how this disease
evolves over time.


Enrico:                 
I fully agree, I fully agree with this message, and [inaudible
00:12:54] but I believe that the traditions that are involved in
[inaudible 00:13:00] maybe can be misleading for other
cardiologists.


Carolyn:              
Nancy, I'm gonna switch tracks a little bit, I mean your
explanation of that already gets me so excited about the kinds of
papers that are gonna get to be seen at the new Circulation Heart
Failure under your leadership. So could you just tell us a little
bit more about your vision as editor-in-chief.


Nancy:                 
Well Carolyn, Circulation Heart Failure is an excellent journal
Dr. [inaudible 00:13:33] has stewarded it beautifully in its
first decade of life. In many ways I don't want to change the
journal, I want the very best science that's helping us have a
deeper understanding of the disease processes and therapies that
affect our patients. That said, I would say we have a couple new
initiatives, or sort of slight differences in how we're going to
manage the journal going forward. I must say, the content we get
is spectacular, and we're so fortunate to be able to look through
the papers we get, and try to choose the very best science. It's
an amazing privilege for me and the new team.


                               
We're really interested in young investigators and those people
who are starting out in their career. The emerging scientists who
are producing the best heart failure science. Early in your
career you might not have the weight of data behind you to merit
publication and circulation proper, but we hope that with good
science well thought out excellent hypotheses, Circulation Heart
Failure will be an appropriate target for those emerging
investigators.


                               
We found some great pleasure in approaching young scientists at
meetings, and discussing their work, and asking them to send it
to our journal. And that's been great fun and we've seen
wonderful yield from that. We've been getting submissions from
people we've spoken to whose work we admire, and we really hope
to build that part of the journal up. Hand in hand with that is
an effort at building our social media presence. We're an
entirely online journal. We're very interested in visually
appealing content. We do have an images in case report section.
And we're going to work to try to build an online community for
our young investigators who may not have the money to travel
internationally, but who really needed global community of heart
failure research colleagues, and we hope to be a place to build
that.


                               
And finally, we're interested in some areas that maybe, are
emerging or underrepresented in other journals. Areas like ...
the way technology is transforming heart failure mechanical
circulatory support devices, wearable devices, the other
technologies we're using increasingly in our patients. And the
world of pulmonary hypertension, and right ventricular
dysfunction, which is sort of searching for a journal home, and
we hope that we can be that journal home. And of course
representing the full spectrum of therapies for heart failures
including transplantation. I already mentioned mechanical
circulatory support, you know, all the richness that is the
evolving field of heart failure, and how we ... I think as
professionals in that field think about and treat our patients a
little differently than other people caring for heart failure.


Carolyn:              
Listeners, you just heard it right here, on Circulation on the
Run.


                               
Thank you so much for joining us this week. Tune in again next
week for even more exciting news.