Circulation January 16, 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. This week's feature paper
takes a deep dive into nitric oxide signaling, that extremely
important pathway in cardiovascular health and disease. This
time, taking a novel look at genetic predisposition, phenotypic
consequences, and therapeutic implications. All that coming right
up after these summaries.


                                               
The first original paper describes the derivation and validation
of a novel model to stratify the risk of death due to circulatory
etiology in patients resuscitated from cardiac arrest without an
ST elevation MI.


                                               
First author, Dr. Bascom, corresponding author Dr. Setter from
Maine Medical Center in Portland and their colleagues use the
International Cardiac Arrest Registry to derive a novel model
termed the CREST Model, which describes an incrementally high
risk of circulatory etiology death with an increasing score.


                                               
Now, CREST is a simple score with components of C for prior
coronary artery disease. R for non-shockable rhythm. E for
ejection fraction less than 30% on admission. S for shock at the
time of admission. T for ischemic time more than 25 minutes. The
authors showed that this CREST tool may allow for estimation of
circulatory risk and improve triage of cardiac arrest survivors
without STEMI at the point of care.


                                               
The next study reports associations between usual sodium,
potassium and blood pressure using gold standard 24-hour urinary
data collected for the first time among a nationally
representative sample of adults in the United States.


                                               
First and corresponding author Dr. Jackson from Centers for
Disease Control and Prevention used cross-sectional data from 766
participants aged 20 to 69 years with complete blood pressure and
24-hour urine collections in the 2014 national health and
nutrition examination survey.


                                               
They found that there was a strong direct relationship between
higher sodium excretion and higher blood pressure and
hypertension. In addition, there was an inverse relationship
between potassium excretion and blood pressure and hypertension.
When added to the evidence based from longitudinal and
interventional studies, these results support clinicians dietary
advise to lower sodium intake and increase consumption of
potassium containing foods.


                                               
The next two studies in this week's journal examine the utility
of circulating biomarkers to aid in the diagnosis of acute aortic
dissection. As a reminder, the AHA/ACC guidelines published in
2010, proposed using the aortic dissection detection risk score
or ADD risk score as a primary screening tool based on scoring
the presence of three categorical risks.


                                               
Number one, high risk conditions such as Marfan Syndrome, a
family history of aortic disease, known aortic valve disease,
known thoracic aortic aneurysm or previous aortic manipulation.
Number two, The pain features such as chest, back or abdominal
pain described as being of abrupt onset severe intensity or
ripping, tearing. Number three, the examination features such as
evidence of profusion deficit, systolic blood pressure
difference, spoken neurological deficit or aortic diastolic
murmur and hypertension or shock.


                                               
The presence of one or more markers within each of these
categorical features is given an ADD score of one with a maximum
cumulative score of three if all three categorical features are
present. In the first of these two papers in this week's journal,
first author Dr. Nazareen, corresponding author Dr. Morello and
colleagues from Molinette Hospital in Italy performed the advised
International Multi Centers Study, which prospectively assessed
the diagnostic performance of standardized strategies integrating
pre-test probability assessment and D-dimer in 1,850 patients
from the emergency department.


                                               
They found that in patients with an ADD risk score above one and
D-dimer less than 500 nanograms per milliliter, the rate of acute
aortic syndromes was significant at one in 22 cases. Rule out
strategies for acute aortic syndromes integrating an ADD risk
score of zero or one with D-dimer less than 500 were found to
miss only around 1 in 300 cases of acute aortic syndrome.


                                               
Integrating the ADD risk score with D-dimer could help to
standardize diagnostic decisions on advanced imaging for
suspected acute aortic syndrome balancing the risks of
misdiagnosis and over testing. The authors concluded that
patients at high probability of acute aortic syndrome such as
with an ADD risk score above one should proceed to computer
tomography and geography or other conclusive imaging irrespective
of D-dimer levels.  However, in those with an ADD risk score
of zero or one, with a D-dimer of less than 500 were possible
rule out diagnostic strategies for acute aortic syndrome.


                                               
The second manuscript in the present issue suggests that soluble
ST2 might be an even better biomarker than D-dimer to rule out
aortic dissection. In this paper by first author, Dr. Wang,
co-corresponding authors, Dr. Du and Guo from Beijing Anzhen
Hospital and Peking University respectively, the authors measured
plasma concentrations of soluble ST2 using the R&D Systems
assay in 1,360 patients including 1,027 participants in the
retrospective discovery set and 330 patients with an initial
suspicion of acute aortic dissection and ruled in a prospective
validation cohort.


                                               
The proportion of acute aortic dissection, this acute chest pain
cohort was high at more than 40%. The authors found that soluble
ST2 measured using this research grade assay showed higher levels
in acute aortic dissection than in acute myocardial infarction or
in acute pulmonary embolism. The result suggested that soluble
ST2 levels could be useful as a rule out marker possibly even to
an extent moderately superior to D-dimer.


                                               
A cut-off level of around 35 nanograms per milliliters using the
research grade soluble ST2 assay appeared to reliably rule out
acute aortic dissection if used within 24 hours after symptom
onset with a negative likelihood ratio of 0.01 and a negative
predictive value of more than 99%. These intriguing findings are
discussed in an accompanying editorial by Dr. Toru Suzuki from
University of Leicester and Dr. Kim Eagle from University of
Michigan. Well, that wraps it up for our summaries. Now, for our
future discussion.


                                               
Nitric oxide signaling plays a key role in the regulation of
vascular tone and platelet activation. In fact, the pharmacologic
stimulation of nitric oxide pathway is emerging as a therapeutic
strategy in cardiovascular medicine in many areas including in
heart failure preserved dejection fraction.


                                               
Today's paper is therefore all the more intriguing because it
seeks to understand the impact of a genetic predisposition to
enhanced nitric oxide signaling on the risk for cardiovascular
disease as a way of informing of the potential utility of
pharmacologic stimulation of the nitric oxide pathway.


                                               
Intrigued? Well, I certainly and I'm so glad to have with us the
corresponding author, Dr. Sekar Kathiresan from Massachusetts
General Hospital as well as a familiar voice, Dr. Peipei Ping,
associate editor from UCLA here to discuss this paper.


                                               
Sekar, could I ask you as an introduction to tell us a little bit
more of the general approach of looking at genetic predisposition
as a way of perhaps forecasting potential utility of
pharmacologic stimulation? Could you tell us a little bit more
about that?


Dr. Sekar Kathiresan:      Yes. I'm
delighted to speak a little bit more about this idea of using
naturally occurring genetic variation to understand if a medicine
developed against a target is going to work in terms of efficacy
and also potentially lead to on target side effect.


                                               
As you know, there are lots of variants for mutations in genes
that eventually become targets for medicines. Over the last 10,
15 years, there's been an explosion in our understanding of human
genetic variation, specifically in genes targeted by medicines.


                                               
The idea here is that if there's a naturally occurring mutation
in that target gene, you can simply ask what are the phenotypic
consequences of carrying that mutation. Also use that information
to predict, as I said, the efficacy of pharmacologic manipulation
and potentially on-target side effects. This approach has become
a very powerful approach.


                                               
A famous recent example of gene, PCSK9, where mutation in this
gene occur naturally. A lower function of PCSK9 and individuals
who carry this mutations have lower LDL levels and lower risk of
heart attack. This information has led to the development of
medicine that mimic those mutations and those medicines have been
proven now to lower LDL as well as lower risk of heart attack, a
phenomenon anticipated by the genetics.


Dr. Carolyn
Lam:              
If I understand it right then, with regards to today's paper, the
idea is that if a genetic predisposition to enhanced nitric oxide
signaling associates with reduced risk of cardiovascular disease,
then that would support the hypothesis that pharmacologic
stimulation of the nitric oxide pathway would prevent or treat
the cardiovascular disease, right? Could you further expand?
Because you also did a meditation analysis. How would we
understand that?


Dr. Sekar Kathiresan:      Let me walk
you through the basics of this paper. Our hypothesis initially
was a genetic predisposition to enhance nitric oxide signaling
would actually affect a range of cardiovascular diseases. Nitric
oxide is a well-known molecule, a regulator of a number of
important processes; vascular tone, blood pressure, platelet
aggregation.


                                               
A couple of important genes in the nitric oxide pathway are, one,
nitric oxide synthase, the key enzyme that generates NO. Second
is a soluble guanylyl cyclase that is a regulatory molecule
involved in NO biology. One of the genes that is part of that
pathway is called GUCY183, which is basically a subunit of the
soluble guanylyl cyclase.


                                               
What we did was we looked at those two genes and asked, "Are
there naturally occurring variations in those two genes that
actually give us a sense that they gain function that they
actually activate nitric oxide signaling. It turned out there are
two polymorphisms. One in nitric oxide synthase and the other is
in the soluble guanylyl cyclase subunit that are essentially gain
of function. They're common polymorphisms.


                                               
We know their gain of function because the carriers of these DNA
variants have lower blood pressure. An indicator that there's
enhanced NO signaling. We use these two polymorphisms as an
instrument to understand the phenotypic consequences of having
lifelong enhanced nitric oxide signaling.


                                               
What we looked at was the relationship of individuals who carried
both of the gene variants or gained a function and asked whether
these individuals what the relationship of carrying the variant
was to a range of cardiovascular diseases as well as a range of
quantitative traits like blood pressure or kidney function.


                                               
We looked at this in extremely large human population samples
where genotype and phenotype had been collated. Most important of
these samples is a recent study of a population-based cohort
study called the UK Biobank, which has involved about a half
million people where genotype and have phenotype have been
assembled.


                                               
What we found was that genetic predisposition to enhance nitric
oxide signaling was associated with reduced risk of several
important cardiovascular diseases. First, coronary heart disease.
Second, peripheral arterial disease, and third, ischemic stroke.


                                               
That provide a very compelling evidence that atherosclerotic
cardiovascular disease would be lower based on enhanced nitric
oxide signaling. What was surprising to us is we also found a
couple of other diseases where it seemed to benefit from enhanced
nitric oxide signaling namely kidney function and pulmonary
function. These were a little surprising to us, but I think it
really suggest that NO plays an important role in a range of
diseases.


                                               
In terms of your question about what aspect of NO biology is
leading to be relationship to these diseases, is it simply the
blood pressure effect for example or could you actually infer a
mechanisms beyond the blood pressure? We looked at that
specifically in the context of cardiovascular disease and we're
able to show that the protection afforded by the enhanced nitric
oxide signaling gene variants, that protection exceeded the
amount predicted by the blood pressure change. In fact, by quite
a bit suggesting that there are probably non-blood pressure
mechanisms that are at play in terms of the protection afforded
by enhanced nitric oxide signaling gene variants.


Dr. Carolyn
Lam:              
Peipei, I have to invite your thoughts now. This is such an
amazing paper. We had great discussions as an editor team. Tell
us your thoughts.


Dr. Peipei
Ping:                
The editorial team as well as the reviewers have been very
impressed with the quality of the datasets and the value and
detail, the metadata analysis together with the appropriate
analytical approach. The study is done in our view in a very
careful manner and the analysis was performed through the highest
standards.


                                               
What we also recognized is the potential impact that this
particular study may have on multiple areas of studies, in
particularly with their findings, the spectrum of individuals,
how they carry nitric oxide signaling trends. You could
appreciate that the individual score or genetic score paired with
the analysis of the genetic variance that they have done, they
see from the mental idea that examine both genetic as well as
phenotype of each individual is critically important for medicine
to be prescribed in the next step of therapies.


Dr. Carolyn
Lam:              
Building on that thought, Sekar, could I ask you? You found some
rare inactivating variance. Are these the patients then you think
should be targeted for NO enhancing therapies? What's the
clinical implications of your findings?


Dr. Sekar Kathiresan:      I think there
are two ways to think about the implications of these findings.
One is there's just a simple biologic insight, the pharmacologic
activation of NO signaling maybe protective beyond pulmonary
hypertension. As you know, there are actually compounds in the
clinic right now that are pharmacologic activators of soluble
guanylate cyclase. Those medicines work in the rare condition of
pulmonary hypertension.


                                               
our work suggest that those medicines are likely to work in a
broader range of indications including atherosclerotic
cardiovascular disease, kidney disease and pulmonary function. At
a simple level, those experiments, I think, should be looked at.
Those indications should be looked at.


                                               
Whether we've identified a subset of a population that
particularly will respond versus it will be a general phenomenon
across a range of different individuals that have impaired nitric
oxide signaling, I think time will tell. Certainly, one group to
think about would be those who are indigenously deficient in
nitric oxide signaling and we did find that there are small
subset of patients who have inactivating mutations in these two
genes and they have higher blood pressure and increased risk for
cardiovascular disease.


                                               
It was a pretty rare phenomenon, so very small number of
individuals would be relevant there. I'm not sure actually that
you necessarily want to limit the potential benefit of NO
signaling, enhanced NO signaling to just that subgroup. In fact,
my prediction would be that the medicine would be relevant for a
very large percentage of the population. That you do not need to
limit the potential application of this therapy to just those who
carry the inactivating mutations.


Dr. Peipei
Ping:                
I agree largely of what Sekar has discussed. I would add that in
situations where genetic information are available with the
patients, what the study has offered is fairly clear in the
patients where rare variance that inactivate the NOS3 or the
guanylyl cyclase off the genes. Maybe a failure it is with a
higher systolic blood pressure risk. I'm entirely supportive with
the general conclusion that we have come to a time point where
NOS outside signaling activation is a critical new element of
therapy in cardiovascular health and disease.


Dr. Sekar Kathiresan:      Thank you
Peipei. Thank you Sekar for taking the time to share your
thoughts with us. We are so proud to be publishing paper in
circulation. So proud and happy to be chatting about this on this
podcast. You've been listening to Circulation on the Run. Thank
you for joining us and please tune in again next week.