Nov 28, 2016
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.