Circulation August 28, 2018 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.


                                               
Do we finally now have a simple, evidence-based way to make a
diagnosis of heart failure with preserved ejection fraction?
Well, today's feature paper certainly brings us closer to that
goal and you must listen to the discussion coming right up after
these summaries.


                                               
Bleeding is commonly cited as a reason for stopping oral
anti-coagulants. However, what is the prognostic significance of
minor bleeding events, or so called nuisance bleeding, in
patients with atrial fibrillation on oral anti-coagulants?


                                               
First and corresponding author, Dr O'Brien from Duke Clinical
Research Institute and her colleagues, identified 6771 patients
with atrial fibrillation in the Orbit AF Prospective Outpatient
Registry. They ascertained nuisance bleeding from medical records
defined as minor bleeding that did not require medical attention.
Overall, 20% had documented nuisance bleeding giving an incidence
rate of 14.8 events per hundred person years. Nuisance bleeding
was not associated with a higher risk of major bleeding, or a
stroke and systemic embolism over the next six months.


                                               
These findings therefore suggest that the occurrence of nuisance
bleeding or minor bleeding should not lead to changes in
anti-coagulant treatment strategies in patients treated with
anti-coagulants.


                                               
The next study sheds new light on mechanisms linking NLRP3
inflammasome activation to atherogenesis. Dr Westerterp from
Columbia University, New York and colleagues studied mice with
myeloid deficiency of ATP binding cassette transporters A1 and G1
and concomitant deficiency of the inflammasome components NLRP3
or caspase-111.


                                               
They showed that cholesterol accumulation in myeloid cells
activated the NLRP3 inflammasome. NLRP3 inflammasome activation
enhanced neutrophil accumulation and neutrophil extracellular
trap formation in atherosclerotic plaques thus accelerating
atherogenesis.


                                               
Patients with Tangier's disease, who had ATP binding at
transporter A1 loss of function, had increased myeloid
cholesterol content and showed markers of inflammasome
activation. Thus, inflammasome activation may underline
cardiovascular disease in these patients.


                                               
The next study identifies TPX20 as a novel transcription factor
regulating angiogenesis. TPX20 is a crucial transcription factor
for embryonic development and its deficiency is associated with
congenital heart disease. However, its role in angiogenesis has
been not been previously described. At least until today's paper
from co-first authors Dr Meng and Dr Gu and co-corresponding
authors Dr Cooke and Dr Fang from Houston Methodist Research
Institute.


                                               
These authors use loss and gain function approaches to explore
the role of TPX20 in angiogenesis both in vitro and in vivo. They
showed that with VEGF stimulation, the transcription factor TPX20
upregulated PROK2 with is secreted from endothelial cells and
gauges its receptor PROKR1 and thereby promotes angiogenesis in
autocrine manner.


                                               
This novel signaling pathway appeared to be highly conserved as
it functioned in zebra fish vascular development and the
angiogenic response to ischemia in a mouse model of peripheral
disease. The authors furthered showed the selective role of TPX20
in endothelial migration but not proliferation. Furthermore,
treatment with recombinant PROK2 the critical effector of TPX20,
improved blood profusion and functional recovery in the mouse
peripheral artery disease model. Thus, these data highlight the
therapeutic potential of PROK2 in augmenting functional
angiogenesis for diseases associated with this regulated
angiogenesis.


                                               
In patients with atrial fibrillation, left atrial appendage
closure with the Watchman device, is known to prevent
thromboembolism from the left atrial appendage. However, thrombus
may still form on the left atrial face of the device, which then
may potentially embolize. This next paper provides important data
on the incidents, predictors, and clinical outcomes of
device-related thrombus after left atrial appendage closure.


                                               
First author, Dr Dukkipati and corresponding author Dr Reddy from
Icahn School of Medicine at Mount Sinai, New York and their
colleagues studied the device arms of 4 prospective FDA trials of
patients undergoing the Watchman implantation. These were the
PROTECT AF, PREVAIL, CAP, and CAP2 trials.


                                               
They found that following percutaneous left atrial appendage
closure with the watchman device, the incidence of device-related
thrombus was 3.7% and this was associated with a more threefold
higher risk of stroke and systemic embolism. Predictors of
device-related thrombus were a history of trans- ischemic attack
or stroke, permanent atrial fibrillation, vascular disease, a
larger left atrial appendage diameter, and a lower left
ventricular ejection fraction.


                                               
Device-related thrombus was not associated with an increased risk
of cardiovascular or all-cause mortality. Nearly 75% of patients
that developed device-related thrombus did not experience a
stroke. And ischemic strokes occurring in patients with
device-related thrombus accounted for approximately 10% of all
ischemic strokes, following left atrial appendage closure. Thus,
given the ramifications of device-related thrombus, a judicious
surveillance strategy using periodic transesophageal echo
cardiography may be considered particularly when risk factors for
device-related thrombus are present.


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


                                               
Heart failure with preserved ejection fraction or HFpEF,
notoriously difficult diagnosis to make, but do we finally have a
validated diagnostic algorithm for HFpEF? Oh, you have to listen
to our conversation today. I am so proud and pleased and thrilled
frankly to have with me today the corresponding author of the
feature paper, and that's Dr Barry Borlaugug from Mayo Clinic in
Rochester, Minnesota as well as editorialist Dr Walter Paulusus
from VU University Medical Center in Amsterdam.


                                               
Thank you so much both of you for making it here. I want to dive
straight into it. So, Walter, maybe could you please paint the
background to this because you wrote I think the most highly
cited diagnostic guidelines of HFpEF, but that was in 2007. Tell
us how does today's paper take us forward?


Dr Walter
Paulus:            
Thank you very much, Carolyn. It's quite an honor for me to give
you comments about this paper, which I think is going to be a
landmark event. Over the years we have seen multiple algorithms
being proposed usually by professional societies like V and C or
the American Society of Echocardiography for the diagnosis of
HFpEF. The major drawback of all these algorithms is that they
have never been validated in clinical practice. And the reason
they have never been validated was that it was extremely
difficult to establish a gold standard for HFpEF.


                                               
And Barry was so clever to already invest in an establishing a
gold standard for HFpEF ten years ago, and he very vigorously
subjected all his patients in whom he suspected HFpEF to an
invasive stress test and could establish the diagonals of HFpEF
using this as a gold standard. And then he used all these
consecutive patients with subsequently used to devise some form
of an algorithm that was immediately validated against a gold
standard. I think this has been a giant leap forwards. And again,
I want to congratulate him with this unique endeavor.


Dr Carolyn
Lam:               
Barry, I want to echo Walter's words and congratulate you. Now,
has it really been ten years in the making? Tell us about this,
Barry.


Dr Barry
Borlaug:             
It has. In fact, it was 12 years ago when we started doing this,
in 2006. But, yeah, these patients were examined in our
laboratory between 2006 when I joined the staff at the Mayo
Clinic to 2016. And really just doing this work up, we kind of
started out doing it on a few patients and then we realized how
powerful the methodology was. We did the invasive exercise
testing with hemodynamics and a larger number of patients and
just through accumulating a large number, as Walter points out,
with a gold standard assessment this allowed us to then determine
which less invasive attributes could be used to identify the
likelihood that heart failure was the diagnosis.


Dr Carolyn
Lam:               
That's so great. But you know beyond just that it is such a
precious data set and so on, your paper is just so beautifully
written and so clinically applicable. You've got this HFpEF score
now for diagnosis. Everybody's going to be talking about it. So
tell us about it. What does HFpEF score? What makes you think
it'll work? How do you apply it clinically?


Dr Barry
Borlaug:             
Thinking about diagnosis a lot, you really have to go back to
[00:19:19] thinking, estimating the probability of disease, and
when you're able to do that then you can find people where you
need to perform really more invasive testing like the exercise
testing. So really, we started like we need to have a better way
to define who needs that more expensive and invasive evaluation.
So we have this large cohort of patients, over 500 patients, 414
in the initial cohort, and then another 100 in the validation
cohort. And they had all undergone this work up, they'd all
undergone very detailed clinical evaluation and pheno typing. And
we hypothesized which characteristics we thought would be most
relevant. And then we did logistic regression to identify all the
predictors.


                                               
There were many things that are associated that you would expect
with HFpEF, but there were only 6 factors in the end in a
multi-variable model that were all independently associated. That
provided the most parsimonious sort of model or score that we
could develop. We included these six different variables. So
there's two for letter H- heavy and hypertensive, and by heavy we
define that as a body mass index above 30. Hypertensive is
defined as two or more antihypertensive medicines. The F in the
H2 HFpEF score is atrial fibrillation, either paroxysmal or
persistence a. Fib. The P is for pulmonary hypertension as
estimated by echo with an estimated PA systolic pressure on
echocardiography of 35. We wanted all of these to be noninvasive
criteria for this score. E is for elder. I specifically didn't
call it elderly because that can be a pejorative term and its
only 60 years which is not that old. So E is elder. And F is for
filling pressures, again estimated by echo doppler cardiography
as an EE prime ratio greater than 9.


                                               
All of the scores are not one point each. They were arranged
based on the strength of correlation in the logistic model. So
being obese, having a BMI above 30 was awarded two points because
it has a strong correlation. Being in atrial fibrillation or
having a history of atrial fibrillation was even stronger at
three points. If you tally these up, the score can range from
0-9, and based on that score you can then estimate a probability
that HFpEF is present, if you're evaluating a patient that meets
the entry criteria of the study, which is basically normal
ejection fraction, and exertional breathlessness.


Dr Carolyn
Lam:               
Nice. Okay, Walter, I think I can safely say that you have been
thinking about this syndrome longer than either Barry or I. So
I'd love your perspectives on how do you think this will be put
into practice clinically perhaps, and where is the key area that
it will change practice compared to perhaps the old diagnostic
algorithms were like?


Dr Walter
Paulus:            
I think this is a very important point, Carolyn. I think this
score is so easy to handle and it is so well validated that we
can now go to general practitioners and cause a general awareness
for the disease. What vies me is that many patients are still
unreported. The reason is that general practitioners and even
general internal medicine people do not realize the [00:19:19]
heart failure with preserved ejection fraction. Now with this
score at hand, we can convince them that there needs to be an
awareness when they see people that have value higher than six on
the score, that they should be suspicious of heart failure being
part of the symptomatology. I think this score mainly has its
usefulness for general practitioners and general internal
medicine.


                                               
Apart from the score, and it's more up to Barry to comment on
this, but I want to highlight also, that he did not only develop
the score, but he also had these very beautiful nomograms which
is more of a find than a score, where he treated the variables in
a continuous way. I think this is fairly useful for cardiologists
and especially for people who want to have acute patients into
trials because here we now have a very refined scale that goes
from 0-160 and that allows you again to see what type of
population you are addressing, what type of patients you are
seeing that eventually what type of patients you are recruiting.
I think for me the HFpEF score is of importance for general
practitioners, general internal medicine, and especially I think
we should also promote the nomogram. The nomogram, I think, are
so refined that it would be useful tool, I think an excellent
tool, for includement into trials.


Dr Carolyn
Lam:               
Oh wonderful. Both of the simplicity and the cleverness, if I
may, of this paper are precious to generalists and cardiologists.
But Barry, I do have a couple of questions for you. Both you
derivation and validation were in Olmsted if I'm not wrong. Now
how am I supposed to apply it to my skinny HFpEF patients in Asia
or elsewhere?


Dr Barry
Borlaug:             
That's an important point, Carolyn. And it's a limitation of the
paper. The people in Olmsted County, MN are not the same as they
are in other parts of the United States or other parts of the
world. I think that additional evaluation and other cohorts are
important. We did the best we could with what we had. We did look
at the patients carefully at Mayo Clinic. People think of it as
quaternary referral center, but a pretty substantial number of
the patients are from the local area, I think about 2/3 of them
were. And when we looked in a subset in a sensitivity analysis of
the people that were more local practice rather than coming from
large academic medical centers, the HFpEF score, or as Walter
pointed out, the continuous HFpEF model performed equally well.
When we looked at people with so-called advanced HFpEF so high
hemopressures at rest versus people at so called early stage
HFpEF the people that have normal hemodynamics at rest but
elevation during exercise. The model also worked well in that
cohort.


                                               
But, like most studies that come out of where I work in
southeastern Minnesota, it is mostly Caucasian people, the mean
BMI was in the low 30s. So we need to look at other populations
to make sure this works elsewhere as well.


Dr Carolyn
Lam:               
Barry, let it go on record that I am your biggest fan. So thank
you so much for this. I was just thinking even in other
populations where the mean BMI may be lower for example here in
Asia, we still definitely see an association with a higher BMI
albeit at a lower cutoff with the presence of HFpEF. So it does
raise this issue of do we need to maybe calibrate the score
differently in different geographies or ethnicities. But that's
not by any way take away from the tremendous input that you've
made.


                                               
One other question is also the strength of atrial fibrillation in
impacting the score. What are your thoughts on the possibility of
misdiagnosis for example atrial fibrillation as HFpEF or the
similar situation since they share symptomatology?


Dr Barry
Borlaug:             
This is a great point, Carolyn. People still sort of argue about
this. Somebody has breathlessness and effort intolerance and
atrial fibrillation. Some doctors say they have symptomatic
atrial fibrillation, but when we put catheters when we take these
patients to the so-called table of truth and put catheters in and
exercise them, we see hemodynamic arrangements that are
diagnostic of heart failure. This led us to believe that this
isn't just symptomatic a fib. It's really HFpEF. And that's why
they have a fib. We published a paper earlier this year in
circulation, more of a brief report, on the association between
atrial fibrillation and HFpEF where we first reported this. That
if you have normal EF, and especially permanent atrial
fibrillation, you can pretty much take it to the bank that the
patient probably does have heart failure with preserved ejection
fraction, at least in the way that we have sort of defined it and
the way that [00:19:19] initially defined it as an inability of
the heart to pump blood adequately at normal filling pressures.


                                               
These patients almost all have that criteria for cardiac failure.
I think that it is a really strong indicator and we probably are
really just like in the general clinics, under recognizing HFpEF.
I think probably in other clinics where people have atrial
fibrillation and effort intolerance, we're again really under
recognizing HFpEF in these people.


Dr Carolyn
Lam:               
Indeed, and it's actually very consistent with Walter, your
recommendations where atrial fibrillation played a big part too.
Do you have any thoughts or advice?


Dr Walter
Paulus:            
My idea is that atrial fibrillation and HFpEF are both
manifestations of the same underlying process, which is systemic
inflammation because of a metabolic disturbance. We used to think
of atrial fibrillation as a consequence of left atrial
dilatation, which itself was caused by the high filling
pressures. I think that this does not hold, there is more to it.
I think the atrium is as sick as the left ventricle and it
undergoes similar pathological changes. That's why the presence
of a fib becomes such a strong determinant of the presence of
HFpEF in Barry's H of HFpEF score. All of this makes a lot of
sense to me.


                                               
I just want to add something else. You spoke about the Asian
population having less BMI and already having HFpEF. I think if
you look at Barry's variables in uni-variant analysis, there's
one which was presence of diabetes or prediabetes which did not
make it in the multi-variant analysis on 0.06. It's my belief
that if you got to the Asian population, that probably the BMI
could be replaced with the presence of prediabetes and diabetes.
Usually the insulin tolerance or insulin resistance is presence
and the BMI is still low. I think there is need for some fine
tuning, maybe in Asian populations, and I think this should be a
challenge to go ahead with it. In fact, I'm leaving for Japan the
day after tomorrow and I'm going to show the slides of Barry's
paper. I'm going to try to set something up to also validate the
score in Japanese populations.


Dr Carolyn
Lam:               
We've got our work cut out for us, Barry! Let's get on to this
too in southeast Asia.


Dr Barry
Borlaug:             
I totally agree with Walter. I think that's great. And Carolyn,
you, in a lot of papers, point this out, that the metabolic,
cardio-metabolic associated with excess body mass, the way we
define it with BMI, is shifted way down in southeast Asian
population, and south Asian population, so I would agree with
Walter's hypothesis that diabetes, prediabetes maybe that's the
better way to go when we look at this in other patient
populations.


Dr Carolyn
Lam:               
You both absolutely made my day with this discussion today. Thank
you so much. What a thrill to be on the same podcast with the
people I admire most.


                                               
Listeners, I know you enjoyed this as much as I did. Don't forget
to tune in again next week.