Circulation July 5, 2016 Issue

Carolyn Lam: Welcome to Circulation on the Run, your weekly
podcast summary and backstage pass to the journal and its
editors. I'm doctor Carolyn Lam, Associate Editor from the
National Heart Center and Duke National University of Singapore.


I am excited to be joined today by 2 guests and we will be
discussing the feature paper on phenotype specific treatment of
heart failure with preserve ejection fraction but first here are
the highlights from 5 original papers in this week's issue.


(0:42) The first paper by first author doctor Haas, corresponding
author Dr. Bidinger and colleagues from Boston Children's
Hospital aim to investigate the role of PCSK9 in nephrotic
syndrome associated hypercholesterolemia. The authors did this by
first looking at 50 patients with nephrotic syndrome and showing
that resolution of nephrotic syndrome was associated with a
decrease in their plasma cholesterol, as well as a decrease in
their plasma PCSK9 levels. They then looked at two mouse models
of nephrotic syndrome. One using nephrotoxic serum to induce
immune mediated damage of the kidney podocytes. The second, a
model of genetic ablation of the kidney podocyte.


In both these models nephrotic syndrome produced
hypercholesterolemia and a 7 to 24 fold induction of plasma PCSK9
levels. The authors then went on to look at the effect of
knocking out PCSK9 both in the whole body as well as specifically
in the liver in these mice. They showed that mice lacking PCSK9
no longer showed the increase in LDL cholesterol with nephrotic
syndrome induced by nephrotoxic serum. Thus in summary, podocyte
damage triggered mocked inductions in plasma PCSK9 and conversely
knocking out PCSK9 in ameliorated this lepodimia in a mouse model
of nephrotic syndrome. The cool thing about this data is that
they now opened the door to the consideration of PCSK9 inhibitors
in patients with nephrotic syndromes associated
hypercholesterolemia.


(2:45) The second paper by Dr. Fortis and colleagues from Duke
Clinical Research Institute aimed to address an important
knowledge gap that has not yet been addressed in the pivotal noac
trials or large registries. Which is whether outcomes differ
among atrial fibrillation papers with worsening renal function
compared with those with stable renal function while taking a
noac versus warfarin. The authors looked a this by studying more
than 12,600 patients who were treated with rivaroxaban compared
to warfarin in the ROCKET AF trial. On treatment worsening renal
function was defined as a decrease of more than 20% from
screening creatinine clearance measurement any time point during
the study.


The main finding was that among patients with on treatment
worsening renal function, rivaroxaban was associated with lower
rates of stroke and systemic embolism compared with warfarin
without an increase in the composite leading end point. This is
really encouraging to all of us who treat these patients, knowing
that it is possible to safely anti-coagulate patients with
worsening renal function without excessive bleeding and to know
that rivaroxaban may be an alternative to warfarin in these
patients. This paper is accompanied by a beautiful editorial on
the multifaceted dilemma of renal function and atrial
fibrillation by doctors Hijazi and Wellington.


(4:30) The third paper by doctor [inaudible 00:04:32] and
colleagues from Massachusetts Journal Hospital describes a
randomized controlled trial of an advanced care planing video
decision support tool in 246 patients with advanced heart
failure. Patients were randomized to an intervention arm which
consisted of a six minute video as well as an advanced care
planning checklist or to a control arm where patients received
only a verbal description of the goals of care. This video began
by first introducing to the patient the concept of advanced care
planning and then using images to depict the three part goals of
care namely, life prolonging care, limited medical care and
comfort care. Patients in the intervention arm who were showed
the video, were more likely to be informed, to select a focus on
comfort and less likely to desire CPR and intubation compared to
patients receiving the verbal information only. The clinical
application of this finding is that advanced care planning video
decision needs can stimulate and supplement patient decision
communication. Indeed we need such tools to enhance patients
understanding of their goals of care options and to ensure that
our patients get care that reflects their well-informed wishes.


(6:10) The fourth paper is by first author Dr. [inaudible
00:06:12] and corresponding author Dr. Lloyd Jones and colleagues
from the Northwestern University Feinburg school of medicine in
Chicago. These authors provided the first prospective evaluation
of atherosclerotic cardiovascular disease outcomes in adults with
heterozygous familial hypercholesterolemia in the US population.
They did this by using individual pool data from 6 epidemiologic
cohorts including more than 68,500 baseline person exams and 1.2
million person years of follow up. They confirmed substantially
elevated long term, meaning up to 30 year risks of coronary heart
disease and total atherosclerotic cardiovascular disease
including stroke in US adults with a familial
hypercholesterolemia phenotype defined as LDL cholesterol above
190 milligrams per deciliter. This was associated with an
acceleration of coronary heart disease risk by up to 20 to 30
years. These findings were independent of other risk factors and
were consistent using various definitions of the familial
hypercholesterolemia phenotype.


What are the clinical implications of these findings? This was
discussed by Dr. Rodriguez and Dr. [inaudible 00:07:47] in an
editorial, the take home message is that there is likely an
important long term burden of atherosclerotic cardiovascular
disease in phenotypic but unrecognized familial
hypercholesterolemia patients in the United States. Current
efforts to identify patterns and gaps in the diagnosis and
management are well justified. The findings also have
implications for risk communication to patients.


(8:20) Finally, the fifth paper is by Dr. [inaudible 00:08:25]
and colleagues of the TIMI study group from Brigham and Women's
Hospital. These authors looked at the impact of renal function on
outcomes with edoxaban and oral factor 10 A inhibitor with 50%
renal clearance compared to warfarin in the ENGAGE AF-TIMI 48
trial. In the pre-specified subgroups of granting clearance 30 to
50 and more than 50 ml per minute. The higher dose edoxaban
regiment was comparable to warfarin for preventing stroke or
systemic embolism and resulted in significantly less major
bleeding. In further exploratory analysis, there was a suggestion
of lower relative efficacy for prevention of stroke or systemic
embolism with the high dose edoxaban regiment, compared to
warfarin in the upper range of creatinine clearance beyond 95 ml
per minute. Due to lower rates of major bleeding, the net
clinical benefit was more favorable with the higher dose edoxaban
regiment across the range of creatinine clearance.


In summary, edoxaban demonstrated superior safety and comparable
efficacy to warfarin for the prevention of thromboembolic events
in many patients with atrial fibrillation. However the authors
were careful to note that there was insufficient evidence to
allow definitive conclusions to be drawn in patients with normal
renal clearance above 95 ml per minute. The authors called for
further investigation of optimal dosing of edoxaban in the higher
range of creatinine clearance.


(10:14) Those were our highlights now for our feature paper of
the week. Phenotype specific treatment of heart failure with
preserved ejection fraction, a multi-organ road map. The first
author is Dr. [inaudible 00:10:31] from Northwestern University
Feinberg School of Medicine in Chicago and colleagues. To discuss
this very special paper today I have two guests, one is a
corresponding author, Dr. Walter Paulus from the VU, University
medical center in Amsterdam as well as Dr. Jarett Berry,
associate editor from UT Southwestern. Welcome Walter and Jarett.


Jarett Berry: Thanks Carolyn.


Walter Paulus: Thank you very much Carolyn.


Carolyn Lam: To start us off this is an in depth review paper and
it is a really very special type of paper that it's new to
Circulation. Jarett could you tell us a little bit about these
reviews and how this paper came to be?


Jarett Berry: As we think about the new Circulation and our goals
to really make the content of Circulation as clinically relevant
as possible, as we think of the different circumstances and
clinically challenges faced by practicing physicians, many
different topics come to mind and one in particular, therapeutic
area heart failure with preserved ejection fraction is one
particular type of cardiovascular disorder that has been very
difficult to find novel treatments for. As we all know there has
been a number of large scale clinical trials that have failed to
improve clinical outcomes in these patients, in situations like
this what we really need is wisdom and a guide from those with
expertise in this area so we can take that wisdom and that
perspective and incorporate it into our approach to caring for
these patients in a way that can provide a road map moving
forward.


This particular review addressing heart failure with preserved
ejection fraction was timely in that sense and the choice of
author, of course, Walter and his colleagues are leaders in the
field in terms of the research and our understanding of HFpEF.
With that goal, we're really trying to reach out to these types
of investigators for these types of reviews to provide us with a
framework to help us think about charging our way forward and we
couldn't think of a more appropriate choice to lead that effort
other than Walter Paulus.


Carolyn Lam: Thank you so much Jarett, that's so well put and I
couldn't agree more. I mean HFpEF is one of those disease
syndromes were guidelines haven't changed in years and basically
the first sentence is that we don't have outcome improving
treatments available. Walter this must have been particularly
challenging and I really congratulate you because one of the
central figures that I'm so impressed with in this review is
actually a clinical application figure and I'm referring to
figure 2. Do you think you could tell the readers a little bit
more about this?


Walter Paulus: I would like to thank first the editors of
Circulation for having given us the opportunity to write this
in-depth review. I must admit before answering Carolyn's question
that I really enjoy this [inaudible 00:13:37]. We have a very
challenging team of co-authors and the most difficult part of the
enterprise was to have all the noses directed in the same
direction. You have to align very many ideas and it has been a
very challenging in-depth but I think it will be teamed out with
a, not a compromise but something, a paper where everybody is
still happy with its content. This is somehow also reflected in
the figure 2 to which Carolyn is alluding.


When we start speaking about the phenotypic diversity, it's very
difficult to [inaudible 00:14:13] with a conceptual theme on how
we're going to organize therapy when there are many different
phenotypes around. I think this is what this figure is all about,
it tries to organize the phenotypic diversity and come up with a
type of personalized medicine for each phenotype in a very
comprehensive way. This figure, in fact, orders the phenotypes,
presentation phenotypes and pre-disposition phenotypes with
presentation phenotypes on the abscissa and the pre-disposition
phenotypes on the ordinate. Then you get a matrix configuration,
you start out in the matrix in the left hand corner for the most
common phenotype which is metabolic risk combined with [inaudible
00:14:59] congestion. Then you go on and you see that you can
have [inaudible 00:15:04] hypertension, then you have additional
measures that need to be taken. You can go downwards in the graph
and then you'll find out that it might be renal dysfunction and
then you find specific measures that have to be taken when renal
dysfunction is present.


By combining the ordinate and the abscissa in the matrix, you
find a very personalized type of therapy for the individual
phenotype. I think this to me what makes the figure that feeling
is that it's structured, it's organized, it's something very
complex in something which is easily comprehensible.


Carolyn Lam: Walter, I have not seen a figure like this that it's
so novel and I know that clinicians will really welcome this
because as Jarett so nicely put, it's wisdom and some sort of
simplification and yet with in-depth understanding that we so
need in the management of this syndrome. Another thing that I
thought was very special about your paper is that you tackled
head on the divergent results of several recent trials. You
described the low nitric oxide, low cyclic guanosine
monophosphate cycle that's present in HFpEF but also try to put
into context the need trial, the relax trial, top cat and even
mention Socrates preserved in all of this. Do you have any quick
top line comments, not to give the whole story away because I'm
sure readers are now encouraged to look at the paper but on how
all of this actually falls into place in your schema.


Walter Paulus: I think how everything falls into place is
illustrated in the figure 1. Figure 1 shows a very broad
perspective on the problems of HFpEF as it shows HFpEF to be the
result of systemic inflammatory state but so far we have focused
only on the project manifestations of the systemic inflammatory
state [inaudible 00:17:08] cardiac manifestations, which is the
stiffness of the myocardium, and the [inaudible 00:17:12] of the
myocardium. There are also things going in the pulmonary
[inaudible 00:17:16], there are things going on in the skeletal
muscle and there are things going on in the kidney. I think that
if you do not take these other organs into perspective, then the
image you will have from the results of your trials is getting
blurred. For instance, we have so many trials about look at the
exercise [inaudible 00:17:35] in terms of elevation of [inaudible
00:17:37].


It's my feeling that many patients with HFpEF just get treated
diabetic. You see them afterwards again in your [inaudible
00:17:46] patient clinic and they have symptoms of nasal fatigue.
They no longer being hindered by the elevation of [inaudible
00:17:52] probably because of the administration of the diabetic
but they're still highly symptomatic and they have moved over to
another board and that limits the [inaudible 00:18:01] mainly the
skeletal muscle. It's of course nicely illustrated already for
years by the work of Dalane Kitzman which is one of the
co-authors, but still these issues, the same goes for the
hypertension, a field in which Carolyn has been very active.
There are some patients who are persistent [inaudible 00:18:18]
hypertension, I'm intrigued by our classification.


It's clear that these patients have moved to a [three catalyst
00:18:24] type of hypertension and we should pay attention to
this and we should try to treat it in a very specific way. Again
[inaudible 00:18:33] the failure of our trials is also
comprehensible. He have two, [inaudible 00:18:38] focus on the
myocardium and we should try to keep a very broad perspective and
look at [inaudible 00:18:43] in major broader way. Just to
support this point is the result of the Socrates reserve trial
which I was very intrigued by it, just listen to the results
couple of days ago at the European Heart Failure Society meeting
in Florence. Turns out if you give this very [inaudible 00:19:01]
patients that there is no change in nature at [inaudible
00:19:05], no change in left atrial dimension, there's no single
argument that something is changing in the myocardium.
Nevertheless the effort tolerance of the patients was greatly
increased and the question is in quality of life, how that has
drastically improved? What I think is going on, is that maybe on
the dose of the [inaudible 00:19:23] you are using this very
[inaudible 00:19:24].


The main effect might be going on the [inaudible 00:19:27] and
you just took the wrong end point, you are again focusing very
narrowly on the myocardium. I think most of the patients have
entered such a trial are relatively stable. You're not going to
put in a trial a patient who is unstable, they must be all be
treated with diabetics and you shift symptoms from the myocardium
to the other organs. I think that the index review which we
provide, I think has 2 main issues, that you should have a broad
perspective on HFpEF with inclusion of the other organs and
secondly, that we provide a matrix configuration for phenotypes
specific treatment.


Carolyn Lam: Walter that is beautifully put and Jarett I think
I'm speaking on behalf of you too that this paper has really
accomplished what our in-depth reviews were aiming to do, which
is to provide a clinical perspective and really insightful
comments regarding the syndrome. Is there anything else you'd
like to add Jarett?


Jarett Berry: Yeah, I just wanted to echo your congratulations
and just to really highlight the importance of this figure 2. I
think it is an important step for us to begin to take the concept
of the heterogeneity the phenotype, whether it's something
happening centrally or peripherally and take that heterogeneity
and try to incorporate that into our practice pattern. I think
that's obviously been discussed in length in literature before
but has not been put together in a practical way for practicing
clinicians. I just want to echo your comments that Walter and his
coauthors have done an important service for all of us as we
think about how to take care of our patients with HFpEF.


Carolyn Lam: That's awesome, I think anyone listening is really
going to want to take hold of that journal and have a look at
both figures, 1 and 2 and read this beautiful paper. Thank you
very much Jarett and Walter for your time, today.


Jarett Berry: Thanks Carolyn.


Walter Paulus: Thank you very much Carolyn, [good night
00:21:20].


Carolyn Lam: You've been listening to Circulation on the Run,
thank you for listening and don't forget to join us next week for
more highlights.