Circulation October 4, 2016 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.


 
 
Today, we will be discussing an interesting Danish nationwide
cohort study on the return to the workforce following first
hospitalization for heart failure, but first here's your summary
of this week's journal.


 
 
The first paper addresses a common question asked by patients who
have survived an aortic dissection. Will this happen to me again?
First author, Dr. Isselbacher, and corresponding author, Dr.
Lindsay, and investigators of the International Registry of
Aortic Dissection investigated this in the largest systematic
analysis to date of patients presenting to hospital with a
recurrent aortic dissection.


 
 
In this large registry, the authors identified 204 patients with
recurrent aortic dissection and compared these to 3624 patients
in the registry with an initial aortic dissection. They found
that patients with recurrent dissection were more likely to have
Marfan syndrome, but not bicuspid aortic valve. Descending aortic
dimensions were greater in those with recurrent dissections than
those with only an initial dissection, and this was independent
of the sentinel dissection type. In multivariable analysis, the
diagnosis of Marfan syndrome was independently predictive of a
recurrent aortic dissection with a hazards ratio of 8.6.


 
 
Furthermore, they found that the patient's age at the time of
first dissection correlated with the anatomic pattern of aortic
involvement. In younger patients, dissection of the proximal
aorta tended to be followed by dissection of the distal aorta,
whereas the reverse was true among older patients suggesting
divergent mechanisms of disease.


 
 
In summary, therefore, this study shows that recurrent aortic
dissection while in common does occur and in fact affected 5% of
those in this registry. The data really illustrate the importance
of syndromic forms of aortic dissection and suggest that
occurrence of a recurrent dissection should raise suspicion of a
genetic etiology of aortic disease.


 
 
The next study provides pre-clinical data suggesting that
counteracting increased hepcidin may be a therapeutic target for
treatment of intracerebral hemorrhage. In this study from first
author, Dr. Xiong, corresponding author, Dr. Yang, and colleagues
from Xinqiao Hospital, the Third Military Medical University in
China, parabiosis and intracerebral hemorrhage mouse models were
combined with in vitro and in vivo experiments to investigate the
roles of hepcidin in brain iron metabolism after intracerebral
hemorrhage. Hepcidin in an important iron regulatory peptide
hormone that controls cellular iron efflux.


 
 
The authors found that increased hepcidin-25 was found in the
serum and astrocytes after intracerebral hemorrhage. In
hepcidin-deficient mice with intracerebral hemorrhage, there was
improvement in brain iron efflux and protection from oxydative
brain injury and cognitive impairment, whereas, the
administration of human hepcidin-25 peptide in these mice
aggravated the brain injury and cognitive impairment.


 
 
In vitro studies showed that increased hepcidin inhibited
intracellular iron efflux in  brain microvascular
endothelial cells, but this phenomenon was rescued by a hepcidin
antagonist. Additionally, toll-like receptor 4 signally pathway
increased hepcidin expression, whereas, a toll-like receptor 4
antagonist decrease brain iron levels and improve cognition
following intracerebral hemorrhage.


 
 
In summary, the study showed that increased hepcidin expression
caused by inflammation prevented brain iron efflux and aggravated
oxidative brain injury and cognitive impairment, thus,
counteracting increased hepcidin maybe a mechanistic target to
promote brain iron efflux and attenuate oxidative brain injury
following intracerebral hemorrhage.


 
 
The next basic science paper provides fascinating insights into
the similarities between advanced atherosclerotic lesions and
tuberculous granulomas, both of which are characterized by a
necrotic lipid core and a fibrous cap. First author Dr. Clement,
corresponding author Dr. Mallat, and colleagues from the
University of Cambridge Addenbrooke's Hospital in United Kingdom
looked at the C-type lectin receptor 4E which has been implicated
in the events leading to granuloma formation in tuberculosis.


 
 
The authors hypothesized that the same C-type lectin receptor 4E
may be involved in the formation of atherosclerotic lesions as
well. They addressed this hypothesis by examining the impact of
receptor activation on macrophage functions in vitro and on the
development of atherosclerosis in mice. They showed that C-type
lectin receptor 4E was expressed within human and mouse
atherosclerotic lesions and was activated by necrotic lesion
extracts. The receptor signaling in macrophages inhibited
cholesterol efflux and induced endoplasmic reticulum stress
responses leading to the induction of proinflammatory mediators
and growth factors.


 
 
Furthermore, repopulation of LDL receptor-deficient mice with
C-type lectin 4E receptor-deficient bone marrow reduced lipid
accumulation, endoplasmic reticulum stress, macrophage
inflammation, and proliferation within developing arterial
lesions that's significantly limiting atherosclerosis.


 
 
In summary, this paper shows that C-type lectin receptor 4E
orchestrates major pathophysiologic events during pluck
development and progression, and thus, provides a mechanistic
explanation for the close association between necrotic lipid core
formation and the development of inflammatory advanced
atherosclerotic lesions.


 
 
The last paper examined the impact of optimal medical therapy in
the dual antiplatelet therapy or DAPT study. In this paper from
first author, Dr. Resor, corresponding author, Dr. Mauri, from
the Brigham and Women's Hospital in Boston and colleagues,
authors sought to assess the impact of optimal medical therapy
use on long term patient outcomes and on the treatment benefit
and risk of continued dual antiplatelet therapy, and they did
this using data from the DAPT study which was a randomized
placebo control trial comparing 30 versus 12 months of final
prudent therapy on the background of aspirin after coronary
stenting.


 
 
Optimal medical therapy was defined as a combination of statin,
beta blocker, and angiotensin-converting enzyme inhibitor or
angiotensin receptor blocker used in patients with an ACC/AHA
class 1 indication for each medication. Endpoints included
myocardial infarction, major adverse cardiovascular and cerebral
vascular events or MACE, and GUSTO moderate or severe bleeding
events.


 
 
Of 11,643 randomized patients with complete medication data, 63%
were on optimal medical therapy. Between 12 and 30 months,
continued final prudent therapy reduced myocardial infarction
compared to placebo in both groups and had consistent effects on
the reduction in MACE, and an increased bleeding regardless of
the optimal medical therapy status. In other words, the P for
interaction was nonsignificant for these comparisons.


 
 
Importantly, patients on optimal medical therapy had lower rates
of myocardial infarction, MACE, and bleeding compared to patients
not on optimal medical therapy. Rates of stent thrombosis in
death did not differ. The take home message is therefore, that
more emphasis on the use of optimal medical therapy after
coronary stenting is needed, but the decision to continue dual
antiplatelet therapy beyond 12 months should be made irrespective
of the optical medical therapy status.


 
 
Those were your summaries. Now, for our feature paper.


 
 
Our feature paper today discusses a really important, but
frankly, often neglected outcome in heart failure, and that is
return to the workforce following first hospitalization for heart
failure, and I'm really pleased to have the first and last author
of this really special Danish paper, Dr. Rasmus Rorth and Dr.
Soren Kristensen, both from the University of Copenhagen, here to
join me today. Hello, gentlemen.


 
Soren:
Hello and thank you for having us, Carolyn.


 
Rasmus:
Hello.


 
Carolyn:
As a very special third guest, we actually have editorialist, Dr.
Martin Cowie from Imperial College London as well. Hi, Martin.


 
Martin:
Hi, Carolyn. Nice to be part of the conversation.


 
Carolyn:
This is going to be so fun. Let's get straight into this. Rasmus,
maybe you could start by telling us. This return to work concept
is hardly addressed in guidelines, it's so important, and yet,
you are one of the first if not the first to take a look at it.
What inspired you to do this?


 
Rasmus:
First of all, we are very inspired to work with heart failure
because heart failure is a common costly, disabling, and deadly
disease, and furthermore, information on young patients with
heart failure is vast.  We know that they have a high
hospitalization rate and a low mortality rate compared to all the
patients. We also know from some of the big trials that young
heart failure patients report low quality of life. Therefore, we
wanted in this study to examine return to work for a number of
reasons.


 
 
First of all, it gives off some information of the patient's
performance basis and we get some information of their quality of
life and mental status, and one more reason that is not that
common for us as clinicians to think about is also for society,
the economic burden these patients play in the society, and all
of these reasons inspired us to get into this exciting field.


 
Carolyn:
I really appreciated that you did this because the patients that
I see here in Asia are on average 10 years younger than the heart
failure patients that have been seen in other European registries
and so on, so it is a very, very important aspect because my
heart failure patients are often the sole breadwinners of
families here. Could you, maybe, Soren, share with us what are
those unique resources that you manage to look at this in such
detail in the Danish registries?


 
Soren:
The unique quality in Denmark is that you have the unique
identifying numbers for all the citizens of Denmark and these
numbers are not only used in the health systems. They're also
used for administrative registries for tax paying and for state
funds and pensions. We were able to link information from the
hospital discharge registries with information on tax paying and
whether or not people are getting pensions. In that way, we could
follow all patients who stayed in Denmark at least to see whether
or not they were receiving any funds, any pension, or sick leave
money, or things like this from the state, or whether they upheld
a position. That's what makes the Danish system a bit unique,
that we have this ability to track the patients across all the
fields of society and also that we have a public health system
which all patients are included in, and the private sector is
negligible in Denmark.


 
Carolyn:
Wow. Listening to that is making all epidemiologist everywhere
really drool. That is such a precious system to look at this.
What were your main findings, Rasmus?


 
Rasmus:
Maybe I should explain a bit about the setting. This is a
nationwide-based study starting where we identify the patient
with the first heart failure hospitalization, 18 to 60 years in
the period from 1997 to 2012, and we followed them onwards. In
our primary analysis, we only included patients in the workforce,
that means either employed or available for the labor market at
time hospitalization. That is the setting of the study.


 
Carolyn:
Could you share your main findings and your take home messages?


 
Rasmus:
Our primary outcome of this study is that after one year, 25% of
the patients did not return to the workforce and we had a low
mortality, only 7% died.


 
Carolyn:
Twenty-five percent didn't return to the workforce?


 
Rasmus:
Yeah, and keeping in mind, Carolyn, these are patients in the
workforce at their first hospitalization and also young patients.
Our take home patient from this paper is that patient in the
workforce at heart failure hospitalization had a low mortality
for the high risk of [inaudible 00:13:41] from the workforce at
one year of followup. Furthermore, we look at some association
effect associated with returning to work, and we found that young
age, male sex, and high level of education were associated with
high likelihood of returning to work.


 
Carolyn:
Martin, you wrote just a beautiful editorial. I have to say I was
chuckling and enjoying it as I read it. I could hear your voice
in it. What do you make of these results in the interpretation?


 
Martin:
I was really pleased to see something published by this really
important topic that is largely ignored, and as you said in your
introduction, the guidelines, if you read them you'll think that
nobody of working age ever develops heart failure. There's no
mention at all about return to work. There's no mention of the
kind of urgent need to be able to provide people with the
counseling about the heart failure and how it might impact their
work, and also, no interaction, no mention of interaction with
employers to tell them, "Yes, this person have this condition,
but actually, could do their job or stay in the same job," or
"How we can help support them?"


 
 
I think this article which is so good to see graded publish in
Circulation and I think we have to see it in the context of other
occupational rehabilitation work which shows that if you don't
get people back to work quite quickly after a major event in
their lives, then you'll never get them back, and that's got huge
consequences for them in their mental health, their economic,
social, family, and never mind the healthcare system. It's really
nice to see this work and I hope many people read it and quote
it.


 
Carolyn:
Martin, you've been to Asia. You know that our patients are
strikingly young, but I wonder, do you think these results are
extrapolatable outside of Denmark?


 
Martin:
I think this comment and not an editorial, Denmark, of course, is
a relatively small country. It's wealthy. It's different from the
states, but it's very different from Asia as you say, so lots of
heart failure patients in Asia are young, of working age, and
quite often, their families depend on them.


 
 
I think the tactics may have to be different to different
countries, but the general principles are the same that we, as a
heart failure team, as heart failure doctors, have to think about
the person not just in terms of the left atrium and left
ventricle, or even of the whole body function, but actually, what
is their role in their family, what are they trying to achieve in
life, how can we support them about way, because otherwise, we're
really failing our patient.


 
 
I think, in Asia even more than in some wealthy, rich countries
where there's a lot of safety nets, it's really important. I'd be
interested in your comment, Carolyn, on what you think we can do
to improve right across the world in terms of occupational rehab.


 
Carolyn:
First, I think it begins with awareness and that's why I just
wanted to tell Soren and Rasmus how much I enjoyed this paper and
I will be citing it because I think it's so important especially
in the younger heart for the community, but can I ask you, Soren
or Rasmus, have these findings changed your practice in any way
or to be even more provocative, do you think that maybe return to
work should be a benchmark to evaluate heart failure programs?


 
Rasmus:
Martin also points out that, first of all, we need to shed light
on this hidden fact of heart failure, and afterwards, I think
it's also a very good policy metrics to use in the future to see
how our patients do.


 
Carolyn:
Are there efforts in Denmark to improve this as a yardstick?


 
Soren:
I'm quite sure that, by large, it's not really registered who is
working, who is not working there. There's not much attention to
it. We're all focusing very much on the performance of the
patient of the NYHA class and so on, so I think we should put
more emphasis on this issue and we should, as Martin also added,
that we should discuss with the patients if they could change
their job or their positions in some ways to better cope if they
lost some of their performance, because we're both think and we
both agree with Martin that it's a huge quality of life to be
able to maintain your job in one way or the other, and we should
definitely put more focus on that, but I'm afraid to say that I
don't think we put much focus on it in Denmark at this time, but
hopefully, we will.


 
Martin:
I think you're right, the attitude have to change across the
world, don't they, and they start with the heart failure team and
the patients because I think most doctors and nurses and patients
assume diagnosis of heart failure, that means really nothing can
be the same again, but we really should be trying to return
people to their optimal function, and I'm sure we can do a lot
more, but perhaps, we need to upscale the workforce and knowing
about the key things about occupational counseling, and maybe
also [inaudible 00:18:30] interact with employers a little bit
more without patient's permission to give them the confidence to
have this person re-enter the workforce in a supported way
because I'm sure the employers value many of these people and
would be pleased to see them still in the workforce.


 
Rasmus:
Exactly. I even think that could be like a fair way of trying to
help the patient by relieving them from their job, which is
actually will be a big mistake for some patients [inaudible
00:18:54] as a physician to help them with making sure they don't
have to return to their job and fill out the statements and
everything, but this may not be the best for the patient.


 
Martin:
Exactly.


 
Carolyn:
Gentlemen, I have enjoyed this conversation so much. Thank you
for taking the time to discuss this very important paper.


 
 
You've been listening to Circulation on the Run. Tune in next
week for more.