Circulation November 29, 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 Dr.
Carolyn Lam, associate editor from the National Heart Center and
Duke National University of Singapore. Our feature discussion
today is about the validation of a novel biomarker-based stroke
risk score for atrial fibrillation, the ABC stroke score. But
first, here's your summary of this week's journal.


 
 
The first paper provides experimental insights into endothelial
nitric oxide synthase uncoupling in endothelial dysfunction. In
this paper by first author Dr. Lee, corresponding author Dr. Wong
and colleagues from Qilu Hospital of Shandong University in
China, authors assessed endothelial function in animal models of
hyperglycemia, hyperhomocysteinemia, and a dyslipidemia. They
demonstrated that GTP cyclohydrolase 1 is the target of the
microRNA-133a and that it's a topic expression and endothelial
cells mediates endothelial dysfunction.


 
 
Furthermore, Lovastatin up-regulated GTP cyclohydrolase 1 and
tetrahydrobiopterin and re-coupled endothelial nitric oxide
synthase in stress endothelial cells. These actions of Lovastatin
were abolished by enforced micro RNA 133A expression and mirrored
by a mir-133a-antagomir. Finally, the beneficial effect of
Lovastatin in mice were abrogated by in vivo mir-133A
over-expression or by GTP cyclohydrolase 1 knockdown. In summary,
this paper offers a mechanistic basis for targeting micro RNA
133A as a therapeutic approach to correct endothelial nitric
oxide synthase dysfunction. It also provides further support to
the role of statins in combating endothelial dysfunction.


 
 
The next study shows us that in hypertrophic cardiomyopathy,
calcium mishandling may be the potential link between the primary
genetic cause and downstream signaling cascade that leads to
hypertrophy and arrythmias. In this study, Dr. Helms and
colleagues from University of Michigan analyzed gene expression,
protein levels and functional essays for calcium regulatory
pathways in 35 human hypertrophic cardiomyopathy surgical samples
with and without sarcomere mutations and compared that with 8
control hearts. They found a marked reduction in circa2
abundance, which correlated with reduced circa2 function in
hypertrophic cardiomyopathy compared to controlled hearts
regardless of the underlying genetic etiology.


 
 
However, calcium calmodulin depend protein kinase type 2 or cam2,
which is a calcium sensing kinase, was deferentially activated
only in the sarcomere gene mutation positive samples. Activation
of chem kinase 2 was associated with an increase in phospholamb
and phosphorylation in hypertrophic cardiomyopathy. However,
neither calcineurin MRNA nor MEF2 activity was increased,
suggesting that calcineurin pathway activation was not an
upstream cause of increased chem kinase 2 protein abundance or
activation.


 
 
In summary, this paper demonstrated that calcium mishandling
occurs through both genotype specific and common pathways in
human hypertrophic cardiomyopathy. Post-translational activation
of chem kinase 2 pathway is specific to sarcomere mutation
positive hypertrophic cardiomyopathy. While Sarco 2 abundance and
sarcoplasmic reticulum calcium uptake are depressed in both
sarcomere positive and negative hypertrophic cardiomyopathy.
Thus, chem kinase pathway inhibition may improve aberrant calcium
cycling in hypertrophic cardiomyopathy. This is discussed further
in an accompanying editorial by Dr. Jill Tardiff.


 
 
The third study suggests that in patients with a dilated aortic
route and trileaflet aortic valve, a ratio of aortic route area
to height provides independent and improved stratification for
prediction of death. First author Dr. Masry, corresponding author
Dr. Desai and colleagues from the Center for Aortic Disease,
Heart and Vascular Institute of Cleveland Clinic, studied
consecutive patients with a dilated aortic route of greater or
equal to 4 centimeters who underwent echocardiography and gated
contrast enhanced thoracic aortic computer tomography or magnetic
resonance and geography between 2003 and 2007.


 
 
A ratio of aortic route area over height was calculated on
tomography and a cutoff of 10 squared centimeters per meter of
height was chosen as abnormal. In 771 patients with trileaflet
aortic valve and concomitant aortopathy, there was incremental
prognostic value for indexing aortic route or ascending aortic
area to patient height rather than using an unindexed aortic
diameter. Incorporation of the ratio significantly and
independently reclassified the risk for death and at normal ratio
was independently associated with higher long-term mortality
while cardiovascular surgery was associated with improved
survival. Importantly, a sizable minority of patients with aortic
route diameters between 4.5 and 5.5 centimeters had an abnormal
aortic route when indexed to height ratio. 78 percent of deaths
in this subgroup occurred in those with an abnormal aortic route
area to height ratio. Findings were similar when ascending aortic
measurements were considered. The take home message is that an
aortic route area to height ratio above 10 squared centimeters
per meter of height has significant and independent prognostic
utility and may be used to re-stratify patients with trileaflet
aortic valve and a dilated aorta.


 
 
The final study provides pre-clinical data to show that
Ticagrelor reduces cardio damage post myocardial infarction to a
greater extent than Clopidogrel by an adenosine induced organ
protective response. First author Dr. Villaher, corresponding
author Dr. Bademan and colleagues from the Cardiovascular
Research Center in Barcelona, Spain studied a close-chest swine
model of ischemia reperfusion in which myocardial infarction was
induced by 1 hour balloon occlusion of the mid-left anterior
descending coronary artery followed by 24 hours of re-flow. Prior
to occlusion, the animals were randomly assigned to receive
either placebo, a loading does of Clopidogrel, a loading does of
Ticagrelor or a loading does of Ticagrelor followed by an A1 A2
receptor antagonist. Edema infarc size left ventricular size and
left ventricular function were assessed by three T cardiomagnetic
resonance imaging. Inhibition of platelet aggregation was the
same between the groups receiving a P2Y-12 inhibitor.


 
 
Yet, Ticagrelor reduced infarc size to a significantly greater
extent than Clopidogrel, reducing it by a further 23.5 percent,
an effect supported by troponin eye assessment and
histopathological analysis. Furthermore, compared to Clopidogrel,
Ticagrelor significantly diminished myocardial edema by 24.5
percent, which correlated with infarced mass. Administration of
an adenosine A1 A2 antagonist abolished the cardio protective
effects of Ticagrelor over Clopidogrel. At a molecular level,
aquaporin 4 expression decreased and the expression and
activation of AMP kinase cyclin and COX-2 increased in the
ischemic myocardium of Ticagrelor versus Clopidogrel treated
animals. In summary, this study shows that Ticagrelor exerts
cardio protective effects beyond its anti-platelet efficacy by
adenosine dependent mechanisms, which reduce necrotic injury and
edema formation. This is discussed in an accompanying editorial
by Drs. Gerbel, Jung and Tantry. That wraps it up for the
summaries. Now for our feature discussion.


 
 
Today, we are going to be discussing the performance of the ABC
score for stroke in atrial fibrillation. And as a reminder for
all our listeners there, ABC stands for A for age, B for
biomarkers, that's NT-proBNP and high-sensitivity troponin, and C
for clinical history of prior stroke. And again as a reminder,
this risk score was originally derived in the Aristotle trial.
However, we have new results about its performance and validation
today from first and corresponding author Dr. Jonas Oldgren from
Uppsala Clinical Research Center in Sweden. Welcome, Jonas.


 
Speaker 2:
Thank you very much.


 
Carolyn Lam:
We also have today the associate editor who managed this paper,
Dr. Sandeep Das from UT Southwestern. Hi Sandeep.


 
Speaker 3:
Hi Carolyn, thanks for having me.


 
Carolyn Lam:
So Jonas, could you start off by telling us why you did this
study and what you found?


 
Speaker 2:
We did this study to validate the recently derived ABC stroke
risk score. We have had risk scores for predicting stroke in
patients with atrial fibrillation derived since the late 1990's
and refined later on. But those risk scores have only used
clinical markers for risk. We have for several years developed
new risk prediction models with biomarkers and now we are combine
them in a very simple biomarker based risk score, taking into
account age as a clinical variable and the clinical history of
prior stroke and only two common used biomarkers. And by that we
can predict the risk of stroke with better precision than
previous clinical risk scores.


 
Carolyn Lam:
Yeah, I like what you said. I mean it is literally as simple as
ABC. So tell us how you validated it and what you found.


 
Speaker 2:
It was derived in a large cohort of patients participating in a
clinical trial with new or relapsed coagulant compared to
Warfarin and we now validated in almost a full size group
participating it another clinical trial. So we have large data
sets of very well described patients where we have good outcome
data. Very solid data to rely on. Now we can see that the ABC
risk score is now validated but the good precision and good
collaboration of the discriminatory abilities is high and better
than the previously used clinical risk scores.


 
Carolyn Lam:
Could you give us some numbers behind that that are clinically
meaningful? Everyone's going to be wondering compared to the
chads-vasc score for example, how does this ABC score perform in
that validation test set?


 
Speaker 2:
We can adjust that by several different aspects. One is of course
to calculate the C index which is a statistical method to see how
good we can predict risk and the C indices for the ABC stroke
score both in the duration and now in the validation cohort is
higher than for the chads-vasc and atrial risk scores. But we can
also look at what we have in this paper in circulation ... we can
look at predicted outcome rates and observed outcome rates and
can see that they clearly overlap both in the duration and
validation court. So if you predict a risk that is less than 1
percent per year, it is observed also a risk that is less than 1
percent a year. Does this always ... the thing is when you derive
risk or but when you validate it in another cohort, you need to
show that it's a similar result.


 
Carolyn Lam:
Yeah, that's true. Sandeep, you are managing this paper. It's
very important. How do you think that clinicians should be taking
the results?


 
Speaker 3:
I think that clearly using anticoagulation and selected patients
at high risk for stroke with atrial fibrillation is one of the
best things we do in cardiology. You know in terms of reducing
the risk of an important harm to patients. I think there's a fair
bit of dissatisfaction out there with currently sort of standard,
which is chads-vasc. Especially in people with a chads-vasc ...
men with a chads-vasc of 1 or women with a chads-vasc of 1 to 2
where there's a bit of struggling over how to decide. So I think
that one real advantage of this score in addition to the fact
that it predicts better by the higher C statistic, which is
fantastic and pretty uncommon, right? Lars sort of buried the
lead a little bit by not emphasizing that it's relatively rare
that we're able to move a c statistic by a point of 5 in the
modern era.


 
 
But the other thing is that it helps give us an ability to come
up with good estimates in people at low risk, which I think has
been a challenge and something that people are a little concerned
clinically. So I think that this is easily available, biomarkers
that we routinely check all the time and it doesn't have the sort
of gender challenge with chads-vasc where you're trying to figure
out whether your low risk woman really needs to be on Warfarin or
anticoagulation. So I think that it has a lot of clinical utility
right out of the box, which is nice.


 
Carolyn Lam:
Actually, Jonas could you let us know is there any sex
differences in the performance of the score?


 
[00:14:46]


Speaker 2:
 


There are no differences in the performance of the score. So we
looked ... the advantage of this score is when we derived it in
the original model, we looked at all important clinical and
biomarker risk factors and we can see that these were the
foremost interesting markers. So we only used those. So we can
predict much better and as pointed out so nicely by Sandeep, for
patients at the lower end of the risk spectrum, we can find
patients or have higher or lower risk even within patients with
chads-vasc 1 or chads-vasc 2. And I think it's also important to
see what about patients at higher risk despite proper
anticoagulation. We did not know how to treat them but in the
future we might perhaps tailor treatment also for those patients
with residual high risk of stroke despite proper anticoagulation
treatment. For instance, if the left atrial appendage occluded
devices are shown in the future to be a good option for those
patients, we can find them also by this risk score. So both in
the higher and lower end of the risk spectrum.


 
Carolyn Lam:
That's a really good point. On that note, I'm just curious. What
do you think is in the future? What more knowledge do we need to
address before we put this into practice or are you already using
this? Or do you think it should enter guidelines for example?
Maybe Sandeep, I could ask for your opinion first.


 
Speaker 3:
We see a lot of biomarkers associated with increased risk kind of
studies come out in the literature. You know probably every week
you see several of these things come out. So what's really
interesting about this is that it's obviously methodologically
extremely well done but its been derived and validated in two
large cohorts, which is pretty much best practice right? You want
to see people validate these risk scores in large and distinct
cohorts of patients to build up sort of clinical validity to the
reader or consumer. So I think, from my standpoint, this is ready
for prime time. I'm really intrigued by the fact that biomarkers,
especially troponin, are predicting stroke in this population and
there have been some observational reports out there that have
showed an association between troponin and increased risk of
stroke or worse outcomes after stroke. So I'd be really curious
as to what Jonas thinks about why troponin would be predictive of
stroke in this population.


 
Speaker 2:
We were extremely intrigued by the finding when we first did
those single observations of only troponin as a risk marker
because we know that troponin is a very specific protein found in
the myocardium. But the clinic predicts risk for stroke also and
there are several explanations but they are mainly hypotheses
about aging and myocardial function really to identify patients
of risk. But the clear cut explanation is still not there.


 
Carolyn Lam:
It's likely that these biomarkers are incorporating aspects that
we don't fully understand, which is why they are better
predictors isn't it? I mean to your point Sandeep.


 
Speaker 3:
Yeah, no absolutely. And I think that's great.


 
Carolyn Lam:
Exactly. It really opens a lot of other questions that need to be
answered in the meantime. Jonas, any other last words about how
you may be applying this clinically in your own patients?


 
Speaker 2:
We have no solid data supporting the use of this clinical risk
score and as already pointed out, which I think is very good, all
clinic risk scores should of course be in the best world
validated as useful decision support truth and really in clinics
trial seeing that they improve outcomes. This is to my knowledge
never been down with a clinical risk scores. We have never used
them prospectively to guide treatment and to improve outcomes.
Actually, we are aiming to do that. We hope to start a clinical
trial next year with ABC score guided treatment compared to
standard of care. But it's a very huge undertake of course to
that we can improve treatment by risk or guided management.


 
Carolyn Lam:
That's excellent. So remember everyone, you heard it right here.
A new trial that they're engaging. I really congratulate you
first for this study, as well as this future efforts which are
clearly going to be very important.


 
 
Thank you very much both of you for joining us today and thank
you listeners for listening. Don't forget to tune in next week.