Circulation February 21, 2017

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. I am so excited to be
discussing the diabetic HFpEF or heart failure with a preserved
ejection fraction phenotype, with world experts and new insights
from the I-PRESERVE Trial. That will just be in a moment and here
are your summaries first.


                                               
The first paper in this issue is a systematic review and
meta-analysis of risk factors for Co-Arctation of the Aorta on
pre-natal ultrasound. In this paper by first author Dr. Familiari
and corresponding author Dr. D'Antonio and colleagues from Arctic
University of Norway, the authors performed a systematic review
of 12 studies on 922 fetuses with echo-cardiography, and found
that those with a post-natal diagnosis of co arctation had
significant differences in several cardiac morphological
parameters compared to cases without co arctation. The presence
of a co arctation shelf, or hypoplastic arch, was associated with
a significantly increased risk of co arctation. Furthermore, they
reported multi-parametric diagnostic models that were associated
with an increased detection rate. Thus, this paper tells us that
assessment of left inflow and outflow tracts prenatally may help
in stratifying the risk of co arctation.


                                               
The next paper reports pre-clinical data that truly represents a
paradigm shift in our understanding of vascular resident
endothelial progenitors in tissue regeneration. In this paper by
first author Dr. Patel, corresponding author Dr. [Cossroterrani
00:02:00], and authors from Royal Brisbane and Women's Hospital
in Australia, the authors studied protein expression levels of
common endothelial markers in mice using flow cytometry. They
discovered an endovascular progenitor cell in vivo that is
present in normal endothelium in the aorta and lungs and
activated in vessel walls during various endogenic situations,
such as in the placenta, skin wound healing, and tumors. They
further define at a molecular level an entirely novel endothelial
hierarchy from an endovascular progenitor cell to a mature
different-shaded endothelial cell via complete RNA sequencing.
They further clarify the linage of endothelial progenitors in
their origin by using bone marrow transplantation and
vascular-specific, lineage-tracing mouse models, showing that the
endovascular progenitor cells were derived neither from bone
marrow nor from hematopoietic progenitors. This discovery of an
endovascular progenitor cell will have significant implications
for the development of endothelial progenitors as a cell therapy.


                                               
The next paper addresses the chicken or egg question regarding
the association between obesity and atrial fibrillation, and this
is done using Mendelian randomization to define a causal
association between body mass index and atrial fibrillation. In
this study by Dr. Chatterjee and colleagues from Massachusetts
General Hospital, the authors looked at more than 50,000 European
individuals without atrial fibrillation at baseline and showed
that genetic variance associated with increasing body mass index
were significantly associated with an increased risk of atrial
fibrillation. The association between genetically determined
obesity and atrial fibrillation persisted even after adjustment
for traditional atrial fibrillation risk factors, such as
hypertension, diabetes, coronary artery disease, and heart
failure. Taken together, these data are consistent with a causal
association between increasing body mass index and incident
atrial fibrillation. These findings therefore support the
primordial prevention of obesity as a significant public health
target to combat the expanding global burden of atrial
fibrillation.


                                               
The last paper provides contemporary estimates of the stroke
burden in China, a country which bears the biggest stroke burden
in the world. In this paper by doctors Wang and Fagen from the
Capital Medical University in Beijing, China and Auckland
University of Technology in New Zealand, and colleagues, the
authors reported results of a nationally represented door-to-door
survey conducted in 2013 in 155 urban and rural centers in 31
provinces in China, totaling 480,687 adults. They found that the
age standardized prevalence was 1,115 per 100,000 people,
incidence rate was 247 per 100,000 person years, and mortality
rates were 115 per 100,000 person years. The stroke prevalence
estimates in 2013 were greater than those reported in China three
decades ago, especially among the rural residents. Finally there
was a north to south gradient of stroke in China, with the
greatest burden observed in the northern and central regions.
Well, that wraps it up for our summaries. Now for our discussion.


                                               
For our featured discussion today, we are talking about my
favorite topic and of course that is HFpEF, or heart failure with
preserved ejection fraction, and I am so thrilled to have with us
today Dr. John McMurray from University of Glasgow, who's the
corresponding author of our featured paper referring to diabetes
in patients with HFpEF and really talking about the novel results
from the I-PRESERVE Trial. Welcome, John!


John
McMurray:              
Thank you Carolyn, it's always a pleasure to speak to you.


Carolyn
Lam:                     
Oh, I have been waiting for this one, and I'm so excited I don't
know where to begin, but how about with this? Diabetes and HFpEF,
first of all, haven't we spoken to death about co-morbidities in
HFpEF? And secondly, what makes this paper special? Because we've
heard about diabetes and HFpEF from CHARM, from DIG, from Relax,
so tell us: why the interest in diabetes and HFpEF?


John
McMurray:              
Sure, Carolyn. I think you and I have been interested in diabetes
and heart failure, that terrible combination, for a long time.
But I think there's a lot more interest in it today because, of
course, we've had several new clinical trials with interventions
to lower blood glucose that have showed both beneficial and
potentially harmful effects on the development of heart failure.
But really what these trials have highlighted is just how common
heart failure is as a complication of diabetes. And we strongly
suspect, though we don't know for sure of course, but we strongly
suspect that most of that heart failure developing amongst
patients with diabetes is probably heart failure with preserved
ejection fractions. So, I think the context currently is that
what's different about our study compared to the ones that you
mentioned is that in I-PRESERVE we measured a number of things
that were not available in, particularly, the large clinical
trials previously. So, in I-PRESERVE we measured natriuretic
peptides, we looked at health-related quality of life, and maybe
most importantly of all we had a large echo-cardiographic sub
study. So I-PRESERVE is quite different than DIG-Preserved and
CHARM-Preserved, and of course a lot larger than the RELAX HFpEF
study.


Carolyn
Lam:                     
I was the associate editor managing your paper and I was so
excited about this that I invited an editorial as well by Brian
Lindman, and he's got this beautiful table that summarizes what
your study really adds to the literature, and I think it's so
critical. Could you start by summarizing? What are the main
findings?


John
McMurray:              
Well, I-PRESERVE, as you know, was a trial of just over 4,000
individuals with HFpEF defined clinically and with an ejection
fraction of 45% or above. There was actually a trial comparing
the angiotensin receptor-blocker [inaudible 00:09:17] placebo,
though in fact there is no difference in morbidity and mortality
between those two treatment groups. So we've looked, as you said,
at the patients who had diabetes and compared those to the
patients who didn't have diabetes. I think there was some very
interesting novel information; if you look at the two subsets of
patients, they actually don't differ in terms of age and sex and,
importantly, in left ventricular ejection fraction.


                                               
But there are other differences that you would expect; for
example, many more of the patients with diabetes were obese. But
interestingly, and despite that, the patients with diabetes had
higher, significantly higher, NT-proBNP levels. So as you know,
obesity tends to be associated with lower rather than higher
natriuretic peptide levels, so here we were finding higher
natriuretic peptide levels in a subset of patients who were
actually, by and large, more obese. And there was no difference
in other things that might have accounted for that difference;
natriuretic peptides, for example, there was no difference in the
proportion of patients who had atrial fibrillation.


                                               
So that was important, and that's also important when we come to
think of outcomes because of course the previous studies
reporting worse outcomes in patients with diabetes had not
adjusted for natriuretic peptides because they by and large
weren't available in the large prior trials. So that, of course,
could have accounted for some of the worse outcome.


                                               
Some of the other things, features, maybe to pick out in terms of
baseline characteristics ... one was that these patients had many
more features of congestion, so patients with diabetes had more
edema, more often had a raised jugular venous pressure and so on,
and that's interesting given some of the recent clinical trial
data that we might come back to. And even though the [inaudible
00:11:22] class distribution was not different between patients
with diabetes and those without, what was very different was
health-related quality of life, which was much worse in patients
with diabetes than those without. Now you could if you chose to,
Carolyn, look at that as saying that physicians weren't assessing
worse functional status or symptomatic status in the patients
with diabetes, but the patients were certainly self-reporting a
much worse health-related quality of life.


                                               
So those were the, sort of, clinical characteristic differences.
We did, as I said, have an echo-cardiographic sub study. There
were 745 patients in total in the trial who had a detailed echo
study, and there were perhaps more modest differences than I
might have expected (and I'd be interested in your opinion about
this) in patients with diabetes. So they had a somewhat greater,
statistically significantly greater left ventricular mass, they
had increased early diastolic mitral inflow velocity through E,
they certainly had increased E over E prime increased left atrial
areas, so there was some left ventricular remodeling and there
was some evidence of increased left ventricular filling pressure,
maybe diastolic disfunction. But the differences were not very
striking; they were there, and as I said previously, ejection
fraction (which most of us regard as perhaps not a very good
measure of systolic function) was similar between the two groups.
We didn't look at more sophisticated and [inaudible 00:13:09]
measures of systolic functions so those could have been
different, we just don't know.


                                               
So that's the baseline clinical features and baseline
echo-cardiographic findings. And then, of course, we followed
these patients for a median of just over four years and what we
found was that the cardiovascular and all cause mortality was
about twice as high in patients with diabetes as in those
without. And if you adjust for conventional clinical variables,
including NT-proBNP, which is individually the most powerful
predictor of outcome, you only very slightly attenuate that
greater risk associated with diabetes. The risk of heart failure
and hospitalization was also about doubled in an unadjusted
analysis, but that was more attenuated in the adjusted analysis.
But you've also got to remember that, of course, the patients
with diabetes were not surviving as long, so the very fact that
they had a substantially higher risk of heart failure and
hospitalization despite a shortened longevity is important.


                                               
Then lastly, again I think a fairly unique aspect of this study
was that we then added the echo-cardiographic findings into the
multi-variable model [inaudible 00:14:33] because it was only a
subset of patients in which we had echo-cardiographic
measurements. The statistical reliability of this is not as
robust as in the main model, but what we saw was that there was
more attenuation of the risk associated with diabetes when you
added in the remodeling and diastolic dysfunction findings that
we saw in the echo-cardiographic sub study. So that's a summary,
I think, of the key points.


Carolyn
Lam:                     
John, I was really impressed and struck by the consistency of the
message, which is what I really appreciated. What you added to
the field was this consistent message that the diabetic HFpEF
just had more signs of fluid overload in general, be it clinical,
be it by NT-proBNP, be it by echo. And I thought that was
something you said it was a moderate difference by echo; it was
enough to be convincing to me, and I really appreciated that. The
fact that adding the echo findings attenuated the significance
... you know we went back and forth about that quite a bit
together, didn't we?


John
McMurray:              
We did.


Carolyn
Lam:                     
I think at the end it is consistent, it is useful information. It
tells me that perhaps some of these outcomes are mediated by this
access fluid, to me, at least part of it. And I think that is how
we ended up expressing it in the final paper.


John
McMurray:              
I think you are absolutely spot on, Carolyn, because I don't
think I had anticipated that the features of congestion would be
so different. And you are correct in that, of course, correlates
very well with natriuretic peptides, with the left atrial
enlargement and so on.


                                               
And then of course (and this is clearly extrapolation) but then
of course it makes one wonder about some of the trials with
diabetes drugs that we've seen. The TZDs, glycosomes, which calls
a little bit of fluid retention, of course precipitating heart
failure, and then the opposite recently with the SGLT2 inhibitors
which of course are diuretics, and those drugs preventing the
development of heart failure.


                                               
And it does make me wonder if the diabetic phenotype maybe was a
little bit of renal dysfunction, some subtle renal dysfunction,
is a sodium and water avid phenotype state and that it doesn't
take very much to tip those patients into frank heart failure and
perhaps we need to think (and I think you might have been
alluding to it) think about insuring that we adequately diurese
these patients given that in this study where people were
supposed to be optimally treated, clearly there was still a lot
of evidence of residual fluid overload.


Carolyn
Lam:                     
I absolutely agree, and yes you read my mind that I was going to
allude to the implications for therapies that have a diuretic
effect, you know, like the SGLP2 inhibitors and in fact this was
discussed in Brian Lindman's editorial, which is a must read.


                                               
Just another question though. What do you think of peripheral
mechanisms contributing to all this?


John
McMurray:              
Yeah, obviously there is the kidney aspect that we saw a
relatively small difference in estimated GFR. Of course that only
tells you one aspect of renal function and the nephron in
diabetes may well be sodium avid maybe more likely to retain
water. So certainly the kidney as a peripheral mechanism might be
very important.


                                               
And then of course the blood vessels, I mean there's no question
that patients with diabetes have more abnormal endothelial
function probably have got enhanced vascular stiffness. And of
course we know from a long time ago at least in HFrEF (I'm not so
sure about HFpEF) but in HFrEF there's evidence that some of the
vascular stiffness you see in patients with HFrEF is actually due
to sodium in the vessel wall and there's some beautiful old-style
clinical physiology experiments showing that if you diurese
patients with HFrEF you restore vasodilation you restore basal
motor responsiveness. It could also be true in HFpEF though of
course patients with HFpEF and many other reasons to have
vascular stiffness.


                                               
So yes, peripheral mechanisms may well be important. Your humoral
abnormalities may be more pronounced in patients with HFpEF and
diabetes compared to those without diabetes. We don't know
because I'm not sure that's been measured very often. Certainly
natriuretic peptides are, but what about things like the
angiotensin system and arginine/vasopressin and the sympathetic
nervous system. You know, there's still so much to study looking
at patients with heart failure with and without diabetes because
they're really quite distinct. And whatever's going on it makes a
big difference the way those patients feel, what they can do, and
what happens to them.


Carolyn
Lam:                     
Yeah, and your study really establishes that. Congratulations
once again John, it's just been such a delight chatting with you.


John
McMurray:              
Likewise, Carolyn.


Carolyn
Lam:                     
Listeners, you heard it right here on Circulation on the Run.
Don't forget to tell all your friends about this podcast and turn
in next week!