Circulation July 31, 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.


                                               
Does measuring baseline BNP add prognostic information in
patients undergoing revascularization for left main coronary
artery disease? Well, to find out the answers, you have to stay
tuned and listen up for our feature discussion coming right up,
after these summaries.


                                               
The first original paper this week reports a new role for bone
morphogenetic protein 9, or BMP9, as an endogenous inhibitor of
cardiac fibrosis. Now, we are familiar with transforming growth
factor beta-one, or TGF-β1, as a promoter of cardiac fibrosis.
TGF-β1 also activates counterregulatory pathways that serve to
regulate TGF-β1 activity in heart failure. BMP9 is a member of
the TGFβ family of cytokines and signals via the downstream
effector protein Smad1.


                                               
In the current paper from first author Dr Morine, corresponding
author Dr Kapur, from Tufts Medical Center in Boston, and their
colleagues. The authors examined BMP9 expression and signaling in
human cardiac fibroblasts and human subjects with heart failure.
They utilized the thoracic aortic constriction–induced model of
heart failure to evaluate the functional effect of BMP9 signaling
on cardiac remodeling. The authors’ results identified a novel
functional role for BMP9 as an endogenous inhibitor of cardiac
fibrosis due to LV pressure overload. They further showed that
treatment with either recombinant BMP9 or inhibiting a high
affinity receptor for BMP9 known as endoglin promoted BMP9
activity and limited cardiac fibrosis in heart failure. Thus,
this provides a potential novel therapeutic approach for patients
with heart failure.


                                               
The next paper shows that endothelial C-type natriuretic peptide,
or CNP, regulates microcirculatory flow and blood pressure. First
author, Dr Špiranec, corresponding author Dr Kuhn, and colleagues
from University of Würzburg in Germany analyzed whether
vasodilating response to CNP changed along the vascular tree. In
other words, whether the guanylyl cyclase–B receptor was
expressed in microvascular types of cells. The authors used novel
gene-modified mouse models to show that guanylyl cyclase–B cyclic
GNP signaling in parasites diminished microcirculatory resistance
and arterial blood pressure. In contrast, endothelial, or
macrovascular smooth muscle cell guanylyl cyclase–B signaling was
not involved. This indicated that CNP participated in the local
cross talk between endothelial cells and parasites, thus playing
an important role in the maintenance of normal microvascular
resistance and blood pressure. Thus, pharmacological augmentation
of endogenous CNP signaling in parasites may provide a useful
therapeutic tool to combat increased vascular resistance and
hypertension.


                                               
Has the rapid and exponential growth in transcatheter aortic
valve replacement, or TAVR, demand overwhelmed capacity, thus
translating to inadequate access and prolonged wait times? Well,
the next paper provides some answers. First author, Dr
Elbaz-Greener, corresponding author Dr Wijeysundera, from
University of Toronto, evaluated temporal transient TAVR wait
times and the associated clinical consequences in their
population-based study of all TAVR referrals from April 2010 to
March 2016 in Ontario, Canada. Their study cohort included 4,461
referrals, of which 50% led to a TAVR, 39% were off-listed for
other reasons, and 11% remained on the wait list at the
conclusions of the study.


                                               
For patients who underwent a TAVR, the estimated median wait time
in the post reimbursement period stabilized at 80 days and has
remained unchanged. The cumulative probability at 80 days of
wait-list mortality was 2% and of heart failure hospitalization,
12%, with an increase in events with increased wait times. Thus,
post reimbursement wait time has remained unchanged for patients
undergoing a TAVR procedure, suggesting that the increase in
capacity has kept pace with the increase in demand. The current
wait time of almost 3 months is associated with important
morbidity and mortality, suggesting a need for greater capacity
and access.


                                               
The final paper shows that patients with type 2 diabetes and a
history of heart failure are particularly likely to benefit from
treatment with the SGLT2 inhibitor canagliflozin. First author,
Dr Rådholm, corresponding author Dr Figtree, from Royal North
Shore Hospital in Australia, and colleagues, studied more than
10,000 participants with type 2 diabetes and high cardiovascular
risk in the CANVAS Program who were randomly assigned to
canagliflozin or placebo and followed for a mean of 188 weeks.
Participants with a history of heart failure at baseline
constituted 14.4% of the study population and were more
frequently women, white, and hypertensive, with a history of
prior cardiovascular disease. The benefit of canagliflozin on
cardiovascular death and hospitalized heart failure was greater
in patients with a prior history of heart failure compared to
those without heart failure at baseline with a p for interaction
of 0.02. The effects of canagliflozin compared with placebo on
other cardiovascular outcomes and key safety outcomes were
similar in patients with and without heart failure at baseline.
Effects were apparent across a broad range of participant
subgroups, including those using established treatments for the
prevention of heart failure, such as
renin-angiotensin-aldosterone system inhibitors, diuretics, and
beta-blockers. Thus, patients with type 2 diabetes and a history
of heart failure may be particularly likely to benefit from
treatment with canagliflozin. The beneficial effects of
canagliflozin on heart failure outcomes unlikely to be accrued on
top of other therapies for heart failure management.


                                               
And that brings us to the end of this week's summaries, now for
our feature discussion.


                                               
In patients with left main coronary artery disease who are
undergoing revascularization, could BNP assessment be that
precision medicine tool to aid us in our clinical decision
making? Well, I am just so excited to discuss this very topic
with the corresponding author for this feature paper, Dr Gregg
Stone from Columbia University Medical Center, as well as our
associate editor and editorialist for this paper, Dr Torbjørn
Omland from University of Oslo.


                                               
Gregg, it was a super smart idea to look at circulating BNP and
how this may associate with outcomes, as well as therapies in the
EXCEL trial. Please tell us what inspired you to do this and
please tell us what you found.


Dr Gregg
Stone:               
As everybody knows, BNP has been identified as an important
prognostic factor in patients with heart failure and ischemic
heart disease. It correlates with both cardiovascular and
noncardiovascular mortality. Patients with left main disease are
among the highest-risk patients that either interventional
cardiologists or cardiac surgeons treat because of the amount of
myocardium at risk, they often present in heart failure, and even
if they're not in overt heart failure, they can be prone to large
severe left ventricular dysfunction. So first we wanted to
establish the prognostic utility of BNP in this patient
population and then we were interested to see if it might have a
role in helping differentiate which patients might have a better
prognosis with either PCI or coronary artery bypass graft
surgery.


                                               
EXCEL is the largest trial to date of left main PCI versus CABG
in a randomized format with 1905 enrolled patients. And overall,
we found that PCI and CABG had similar rates of deaths, large
myocardial infarction, or stroke in 3 years. But of course, there
are high risk-patients and low-risk patients buried within those
overall aggregate outcomes, and BNP was an important prognostic
predictor of overall mortality in the trial. Both cardiovascular
and noncardiovascular, but not of any other ischemic end points
interestingly. Not myocardial infarction, stent thrombosis, graft
occlusion, bleeding, revascularization. But definitely,
mortality. Even independent of left ventricular ejection fraction
and heart failure status.


                                               
Now, when we looked at the outcomes of PCI versus bypass surgery,
we actually found a very powerful interaction, such that at
relatively lower BNP levels, patients who underwent PCI had a
better prognosis and tended to have lower mortality. Where
patients with high baseline BNP levels tended to have a better
prognosis after surgery.


Dr Carolyn
Lam:               
You know, Torbjørn, I love your editorial where you contextualize
these findings so nicely. Could you do that for us now?


Dr Torbjørn Omland:      First, I would
like to congratulate Gregg and his team with this very
interesting and very well-done study, and I think Circulation is
very fortunate to be able to publish papers like this. We have
known for quite a long time that BNP is a strong prognostic
indicator across the spectrum of cardiovascular diseases and it
seems to be particularly strongly associated with risk of heart
failure events, cardiac arrhythmias, and risk of death. And, as
shown in the EXCEL trial, the association with left ventricular
ejection fraction is actually quite weak, and also the
association with ischemic events. So, these findings fit very
well with previous observations. The really novel and intriguing
finding of this study is the very strong interaction between
procedural BNP levels and the effect of the randomized therapies
and, as you alluded to, all the investigators have tried to look
at this in other more low-risk populations like in the LIPID
trial but actually failed to find any significant interaction.
It's really a novel and important finding.


Dr Carolyn
Lam:               
That's true. Does it bring up the question are the natriuretic
peptides just a better EF measurement? You mentioned that there
was a correlation, what do you think, Gregg?


Dr Torbjørn
Stone:         
Well, you know, there was a weak correlation between BNP and
ejection fraction and history of heart failure but the prognostic
utility of BNP in this study and its ability to differentiate
between the outcomes of PCI versus CABG in patients with low
versus high BNP was actually strongly independent of both
congestive heart failure history and acute left ventricular
ejection fraction. So, I think the BNP is giving a useful
independent information. It's a strong reflector of both atrial
and ventricular pressures and volume status, but it also reflects
myocardial hypoxia, it may be involved in glycolysis and lipid
peroxidation, and other mechanisms that we don't fully
understand. There may be elements of diastolic dysfunction that
we have not measured in this study and other mechanisms related
to prognosis in these patients. So, while EXCEL was not set up to
truly differentiate and delve deeply into the mechanisms of our
observations, statistically these were strong associations that
may prove clinically useful.


Dr Carolyn
Lam:               
Right, I thought that was so intriguing as well, just the points
that you brought up. First, let's just clarify for the audience
that when you say low and high you were using a cutoff of 100.


Dr Gregg
Stone:               
We did use a cutoff of 100 pg per mL as is common, but we also
modeled BNP as a continuous measure. And actually the
relationships were even stronger when modeled as a log hazard
ratio continuous measure, both for mortality and for the primary
end point.


Dr Carolyn
Lam:               
Yeah, that's so cool. And Torbjørn, you talked about this in your
editorial as well and I thought your point about the
distributions of the ejection fraction versus the distribution of
natriuretic peptide, that was very revealing, too. Would you like
to explain your thoughts there?


Dr Torbjørn Omland:      I found it very
interesting that all of this is clearly a high-risk operation
overall. More than 90% actually had what we regard a normal, or
at least not a reduced ejection fraction. Whereas the
distribution of BNP values were more widely distributed so that
actually about 40% of participants had BNP levels above this
ratio of 100 pg per mL. And that probably shows that in this
population, BNP provides additional and independent information
about the status of the myocardium that is not revealed by
angiography or ejection fraction measurements.


Dr Carolyn
Lam:               
That's true, and that's an important point because it added above
the SYNTAX score, too, right Gregg?


Dr Gregg
Stone:               
That's right, it was an independent predictor, and in fact the
SYNTAX score and the severity of left main coronary disease did
not vary, according to BNP levels, that is. High versus low BNP
were equally distributed, not related to the anatomic extent and
complexity of coronary artery disease. So, BNP is clearly
reflecting a different state of the myocardium in a way that we
can't measure with any other available test and that makes it
quite a useful biomarker.


Dr Carolyn
Lam:               
Exactly, so I think I'd like to wrap up with asking you both, you
can already see what the potential clinical implications are,
right? Which means that perhaps in a similar type of patient
where there's equipoise of the revascularization method and has
left main disease, maybe we should be using natriuretic peptides
to guide our clinical decision making. What do you think are next
steps before this is prime time?


Dr Gregg
Stone:               
Well I can mention that when one makes a decision of the best
revascularization modality for patients with extensive
multi-vessel or left main coronary artery disease, there are many
factors that go into that determination, both clinical, anatomic,
is the patient a good candidate for one versus the other
revascularization modality, what are the patient's preferences,
what's the surgeon's or interventionalist's likelihood of being
able to safely get the patient through the procedure and achieve
complete revascularization.


                                               
The SYNTAX score makes a difference, as does gender and age and
kidney disease and COPD and ejection fraction and many other
factors. So I think we can now add to that list BNP, although I
will say this was a post-hoc study, we only had BNP available in
approximately 60% of the patients, and while the outcomes were
similar in the patients who we did not versus who we did have
BNP, this has to be looked at as hypothesis-generating analysis,
and we would love to also see this type of finding replicated in
other large datasets. That being said, there are no other large
left main or new multi-vessel disease trials that are planned
right now to my knowledge, and I think given the breadth of this
dataset and its size and scope, I do think that these findings
are robust enough to use BNP as one of the clinical factors to
consider in revascularization decisions.


Dr Torbjørn Omland:      I actually
agree with that and I think ideally, we would, of course, like to
see external validation in another dataset and even retrospective
randomized study comparing conventional versus BNP-guided
strategy but that may not be realistically undertaken. So, I
think these are clearly the best data we have and as clinicians
need to integrate this in our overall evaluation in making this
important decision.


Dr Carolyn
Lam:               
Yeah, I mean Gregg, could I ask you, do you apply this clinically
already?


Dr Gregg
Stone:               
We have not been before this, although I believe we will now. I
believe BNP should be a biomarker that we more routinely measure
in patients with ischemic heart disease as well as those with
overt congestive heart failure. And again, use as one of the
factors of many when making revascularization decisions. And I
think it's important to note also that the PCI patients tended to
preferentially benefit, in fact with even lower mortality when
BNP was lower. Where the surgical patients tended to benefit when
BNP was higher. So, it's one factor, not the only factor, but I
think it's one additional piece of the puzzle.


Dr Carolyn
Lam:               
Yeah, I have to say too I mean, after reading this, after reading
this awesome editorial, it's hard not to think I should be
applying this clinically because it's going to be really hard and
take a long time to prove this with more prospective data, for
example. Although, external validation and other datasets may be
better, this is the largest trial already to show this and show
it so clearly with a significant interaction. I think that is
striking to me.


                                               
Torbjørn maybe I've put you on the spot with the last word, does
this change your clinical practice?


Dr Torbjørn Omland:      I agree with
Gregg. This will be one of maybe several other factors but I
think it's ready for being taken into account when making this
sometimes very difficult decision.


Dr Carolyn
Lam:               
Thank you so much Gregg and Torbjørn for joining me today. You've
been listening to Circulation on the Run. Don't forget to tune in
again next week.