Circulation September 12, 2017 Issue

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. Our feature paper this
week contains novel data from the TOPCAT trial, this time
relating physical activity to prognosis in patients with heart
failure and preserved ejection fraction. A great discussion
coming right up after this weeks' summaries.


                                               
Our first paper tells us that pericarditis may be a marker of
occult cancer and augurs increased mortality following the cancer
diagnosis. Authors, Dr. Sogaard and colleagues from our host
university hospital in Denmark used the Danish medical databases
to conduct a nationwide cohort study of all patients with a
first-time diagnosis of pericarditis from 1994 to 2013. Among
13,759 patients with acute pericarditis, 1,550 subsequently were
diagnosed with cancer during followup.


                                               
Patients with newly-diagnosed pericarditis had higher risks than
age and sex match members of the general population of being
diagnosed with lung cancer, Non-Hodgkin lymphoma, and myeloid
leukemia during the first three months following a pericarditis
diagnosis, but increased risks for lung cancer and Non-Hodgkin
lymphoma and bladder cancer persisted beyond one year following a
pericarditis diagnosis. The increased cancer risk was not
restricted to patients with pericardial effusion.


                                               
Furthermore, pericarditis was a prognostic factor for survival
after lung cancer, breast cancer, and bladder cancer. Thus, the
clinical take-home message is that patients with pericarditis,
particularly when complicated by pericardial effusion, may need
to be considered for workup targeted at diagnosing or ruling out
cancer.


 


The next paper provides insights into mechanistic processes
leading to stent thrombosis in the largest contemporarily
available series of patients undergoing optimal coherence
tomography, or OCT imaging, during stent thrombosis presentation.
The first author, Dr. Adriaenssens, corresponding author, Dr.
Byrne from Munich, Germany, and colleagues of Prestige
Consortium, performed a prospective multicenter study to evaluate
OCT findings in consecutive patients presenting with stent
thrombosis enrolled in a registry that was using a centralized
registration system.


                                               
In 231 patients with stent thrombosis undergoing OCT, uncovered
and malapposed struts were frequently observed, with the
incidents of both decreasing with longer time intervals between
stent implantation and presentation. The most frequent dominant
observation varied according to the time intervals from index
stenting. Uncovered struts and stent underexpansion were the most
common observations in acute or subacute stent thrombosis,
whereas neoatherosclerosis and uncovered struts were the most
common findings in late or very late stent thrombosis. The impact
of dedicated clinical strategies for the prevention and treatment
of mechanisms underlying stent thrombosis should be investigated
in future clinical studies.


                                               
The next study identifies a new type of capillary malformation,
arteriovenous malformation. Now, we know that most arteriovenous
malformations are localized and occur sporadically. However, they
also can be multifocal in autosomal dominant disorders, such as
hereditary hemorrhagic telangiectasia and capillary malformation
arteriovenous malformation or CMAVM. RASA1 mutations have been
identified in 50% of patients with CMAVM.


                                               
In the current study, first author, Dr. Amyere, corresponding
author, Dr. Vikkula from Brussels, Belgium and colleagues studied
non-RASA1 patients and found that EphB4 mutations occurred in
patients with multifocal capillary malformations associated with
arteriovenous malformations. This phenotype named CMAVM2 mimicked
RASA1-related CMAVM1 and also hereditary hemorrhagic
telangiectasia. RASA1-encoded p120-RasGAP was a direct effector
of EphB4. Furthermore, the study implicated EphB4-RAS-ERK
signaling pathway as a major cause of arteriovenous
malformations. Thus, patients with multifocal capillary
malformations need to be screened, not only for an inherited
RASA1 mutation, but also for EphB4.


                                               
The final study identifies a novel potential therapeutic target
in the treatment of atherosclerosis, and that is Dickkopf-related
protein 3, or DKK3, a secreted protein previously known for its
involvement in the regulation of cardiac remodeling and vascular
smooth muscle cell differentiation, but very little studied in
atherosclerosis. In the current study, first author is Dr. U.N.
[inaudible 00:05:51], corresponding authors, Dr. Qu from Capital
Medical University in Beijing, and Xu from Kings College London
used both epidemiological and experimental approaches to test the
hypothesis that DKK3 was atheroprotective.


                                               
In the prospective population-based Bruneck study, they found
that the level of plasma DKK3 was inversely related to carotid
artery intimal medial thickness and five-year progression of
carotid atherosclerosis independently from standard risk factors
for atherosclerosis. Experimentally, they demonstrated that DKK3
promoted re-endothelialization in murine models of
atherosclerosis and wire-induced femoral artery injury, thus
revealing its atheroprotective role.


                                               
They further explored the mechanism of DKK3-induced endothelial
cell migration, which was via noncanonical Wnt signaling
pathways.  The study, therefore, provides the evidence for a
role of DKK3 in the protection against atherosclerosis involving
endothelial migration and repair with potential therapeutic
implications.


                                               
That wraps it up for our summaries. Now for our feature
discussion.


                                               
For today's feature discussion, we are talking about physical
activity and prognosis in heart failure with preserved ejection
fraction, or HFPEF. To discuss this paper, which contains really
neat results from the TOPCAT trial, we have none other than the
first author, Dr. Sheila Hegde, corresponding author, Dr. Scott
Soloman, both from Brigham and Women's Hospital, as well as Dr.
Jarett Berry from U.T. Southwestern, who was the editorialist on
this paper. Welcome, everyone.


Dr. Scott
Solomon:         
Thanks, Carolyn.


Dr. Sheila
Hegde:            
Thank you.


Dr. Jarett
Berry:               
Thank you, Carolyn.


Dr. Carolyn
Lam:              
Hey, Scott. Could you set the background a little bit and let us
know what was the rationale of looking at physical activity in
TOPCAT?


Dr. Scott
Solomon:          As
you well know, heart failure with preserved ejection fraction is
a disorder in which we don't currently have a therapy, or for
which we currently don't have a therapy, and we know that people
would also have a lot of comorbidities. Sheila has been extremely
interested in the role of physical activity in heart failure and
patients with heart failure, has studied this in the
atherosclerosis risk in community studies, and we thought TOPCAT
would be a great overall trial dataset to understand the
importance of physical activity in HFPEF patients and the
relationship with outcomes.


                                               
As you know, TOPCAT is a study that was funded by the NIH in
patients with heart failure, preserved ejection fraction.
Patients were randomized to spironolactone or placebo and then
followed for outcomes, and it was a very rich dataset for which
we have a lot of physical activity information.


Dr. Carolyn
Lam:              
Indeed, and I wasn't even aware of the extent of the physical
activity information in TOPCAT. Sheila, could you explain a bit
how physical activity was captured and graded, and tell us about
your findings?


Dr. Sheila
Hegde:            
Each participant’s physical activity was assessed by self report.
Subjects were asked about the amount of heavy, medium, and light
exercise in the preceding two weeks. They were given some
examples of what those might be and what we did was, we converted
these to AHA, American Heart Association categories of poor,
intermediate, and ideal activity. As you know, the ideal activity
category corresponds to 150 minutes of moderate intensity
activity per week or 75 minutes of vigorous activity per week.
What we found, using these categories, was that the majority of
subjects actually met criteria for poor activity, so at least
75%. Also, a majority were New York Heart Association Class II
heart failure.


                                               
Those with poor activity were more likely to be women, have
diabetes, chronic kidney disease, and a previous history of heart
failure hospitalization. Interestingly, there was no significant
difference in history of myocardial infarction, stroke, atrial
fibrillation, or COPD. The median follow-up time for this group
was 2.4 years, and we did sort of focus on the first two years
because there was an interaction with times and randomization
and, using Cox regression models, we found that those with poor
or intermediate activity had approximately a two-fold higher risk
of a primary composite outcome, which was heart failure
hospitalization, cardiovascular mortality, or aborted cardiac
arrest.


Dr. Carolyn
Lam:              
Wow! You know what the question is? Chicken or egg? Does this
mean those who were exercising had better outcomes or they were
just better and, therefore, they could exercise?


Dr. Sheila
Hegde:            
That's a very good question. This is a post hoc analysis, so it
will be difficult to say, but we did sort of look at excluding
those with a history of stroke or MI and found that the same
two-fold increased risk of outcomes existed for those with poor
intermediate activity.


Dr. Scott
Solomon:         
This is always the problem, as you know, Carolyn, with
observational data. We don't know if the patients who are
exercising more are doing better because they're exercising more
or is it that the people who feel better can exercise more? You
try to adjust as much as you can, but I don't know that there's
any way to determine that for sure without doing a randomized
trial of exercise in patients with HFPEF.


Dr. Carolyn
Lam:              
Certainly and, in fact, I thought that was one of the good
messages, that it's time that we do a proper trial of that, don't
you think? Jarett, would you have some questions for Sheila and
Scott, too?


Dr. Jarett
Berry:               
I was really interested in your figure 3, this dose response
analysis. In figure 3, you divided the exposure into deciles. You
don't begin to see a decremented risk until you begin to see the
ninth and tenth decile of exercise. If you look at other
observational data, you really see this different pattern where
just getting off the couch seems to be beneficial in other
observational data for preventing coronary disease events but,
both in our work and also in this paper here, particularly your
figure 3, you see that this higher dose of physical activity was
required to see a reduction in risk. I don't know if you could
comment a little bit on that.


Dr. Sheila
Hegde:            
I agree that there is a difference in what appears to be a dose
response at lower levels of activity. In this analysis, we
actually included amount of light intensity of activity since the
majority of people had no moderate or vigorous intensity activity
to account for. In that sense, there's even sort of a higher
threshold, perhaps, required to achieve benefit and reduction of
risk, and it may be that heart failure has a different mechanism
for physical activity in terms of achieving those benefits.


Dr. Jarett
Berry:               
I'm wondering, I guess getting back to Carolyn's original point
there about, and Scott's comments, as well, about the need for a
trial. If you look back at HF-ACTION where we saw some relatively
modest benefit for exercise training and heart failure with
reduced ejection fraction. Some of our prior work would suggest
that, actually, the benefit of exercise is much more apparent in
HFPEF patients. When you train HFPEF patients, they tend to
improve much more dramatically with regard to VO2 peak, compared
to heart failure with reduced ejection fraction. I'm just
wondering what your thoughts were about the next steps. It seems
like a trial of some type would be of great interest. What are
your thoughts about that?


Dr. Scott
Solomon:          I
agree with you 100%. It would be a great idea for a trial. There
have been small trials, as you know. Dalane Kitzman did a trial
and Frank Edelmann and Burkert Pieske did a trial, and I think
they're actually even doing another one now. The relatively small
numbers of patients do show improvement in myocardial oxygen
uptake, improvement in quality of life, and some improvement in
some measures of echocardiographic measures of diastolic
function, as well, with exercise training which is, frankly, more
than we've gotten with drug therapies, so I agree 100%.


                                               
It's also important to note that it's actually hard to get our
patients with HFPEF in the United States into cardiac rehab
because it's currently not paid for by Medicare, and I'm hoping
that will change, as well.


Dr. Carolyn
Lam:              
You know, that's so well put, Scott. I've got a question, though.
Every time you think TOPCAT, you think regional variation, right?
How did this look in the different regions, in the U.S. versus
elsewhere?


Dr. Scott
Solomon:         
First of all, let me just tell the audience that TOPCAT was a
study in which we enrolled patients both in the Americas, which
was the U.S., Canada, Argentina and Brazil, and in Russia and the
Republic of Georgia. As you know, when we unblinded the trial, we
found that the event rates in Russia and the Republic of Georgia
were considerably lower, about five-fold lower than they were in
the Americas. We believe that many of these patients may not have
had heart failure.


                                               
We've also recently found that many of these patients probably
weren't taking spironolactone, as well. For many of our TOPCAT
analyses now, including this one, we excluded the patients in
Russia and Georgia and just focused on the Americas. Sheila, did
you happen to look at the results in Russia and Georgia, just as
a tweak?


Dr. Carolyn
Lam:              
I can tell you that the majority of patients were active, so very
much different than our majority in active patients in the
Americas region.


Dr. Jarett
Berry:               
This is an amazing study that really puts forward an important
hypothesis that needs to be tested. Before, I know we've
discussed that a couple of times already, but I really believe
that we are exercising the wrong heart failure patients. As the
Director of Cardiac Rehab here at Southwestern, we are including
a lot of heart failure with reduced ejection fraction but, as
Scott points out, there aren't currently funding available or
billing is not allowable for patients who have heart failure with
preserved ejection fraction.


                                               
I think it's only studies like this that are going to move the
field for it and how we can begin to think about caring for these
patients and treating their comorbidities and treating their
disease process through what we believe is probably one of the
most important therapeutic strategies we have that we're not
using, and that would be the exercise training, so I think this
is a fantastic study and a wonderful contribution as we begin to
think more about the future of treatment for patients with HFPEF.


Dr. Carolyn
Lam:              
Thank you so much, everyone. Listeners, I'm sure you enjoyed that
conversation as much as I did. Don't forget to tune in again next
week.