Circulation May 30, 2017 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. Our featured paper this
week confirms the clinical utility of a polygenic risk score of
common variants of cardiovascular disease. More soon after this
week’s summary of articles.


                               
The first original article describes distinct cell-specific roles
for NADPH oxidase, or Nox2, in blood pressure regulation. This
paper from first author, Dr. Sag, corresponding author, Dr. Shah,
colleagues from King's College London British Heart Foundation
Center of Excellence in the United Kingdom. The authors used
novel gene modified mouse models to show that Nox2 in myeloid
cells modulates basal blood pressure whereas endothelial cell
Nox2 is involved in angiotensin II-dependent hypertension. The
finding that Nox2 in different cell types has distinct effects on
blood pressure, suggest that different diseases conditions may
alter blood pressure through effects on Nox2 in different cell
types. For example, it is conceivable that the effects on myeloid
cells on basal blood pressure may be enhanced in inflammatory
settings, whereas endothelial cell Nox2 activation may be more
relevant to renin-angiotensin system-dependent hypertension. The
current results are therefore relevant to the design of novel
therapeutic approaches for hypertension by targeting NADPH
oxidases.


                               
The next paper provides a new, more accurate atherosclerotic
cardiovascular disease risk prediction tool in familial
hypercholesterolemia that may increase the efficiency of care and
use of newer lipid lowering therapies. Co-corresponding authors,
Dr. Mata and Pérez de Isla, from Hospital Clinicals San Carlos in
Madrid, Spain, use data from SAFEHEART, a multicenter,
nationwide, long-term prospective cohort study of 2,404 adult
patients with molecularly-defined familial hypercholesterolemia
and who have followed up for a mean of 5.5 years. They developed
a robust risk prediction equation for incident atherosclerotic
cardiovascular disease based on the following independent
predictors; age, male gender, history of previous atherosclerotic
cardiovascular disease, high blood pressure, increased body mass
index, active smoking, LDL cholesterol and LPA levels. The new
SAFEHEART risk equation performed better with a Harrell C index
of 0.81 compared to 0.78 for the modified Framingham's risk
equation and 0.8 for the ACC/AHA Pooled Cohort risk Equations.
The authors therefore concluded that the risk of incident
atherosclerotic cardiovascular disease may be estimated in
familiar hypercholesterolemia patients, using simple clinical
predictors, and that these findings may improve re-stratification
and could be utilized to guide therapy in patients with familiar
hypercholesterolemia.


                               
The next study tells us that late gadolinium enhancement
cardiovascular magnetic residents identifies patients with
dilated cardiomyopathy but without severe left ventricular
systolic dysfunction, who are still at high risk of sudden
cardiac death. In this study, by first author Dr. Halliday,
corresponding author Dr. Pennell, from Royal Brompton Hospital in
London, United Kingdom, the authors prospectively investigated
the association between mid-wall late gadolinium enhancement and
the primary composite outcome of sudden cardiac death or aborted
sudden cardiac death, among 399 consecutive referrals with
dilated cardiomyopathy and a left ventricular ejection fraction
above 40% seen at their center between 2000 and 2011. These
patients were followed for a median of 4.6 years. 17.8% of
patients with late gadolinium enhancement reached the
pre-specified end point, compared to only 2.3% without late
gadolinium enhancement.


                               
Furthermore, following adjustment, late gadolinium enhancement
predicted the composite end point, with a hazards ratio of 9.3.
Thus, patients with dilated cardiomyopathy and mid-wall late
gadolinium enhancement, and mild or moderate reductions of left
ventricular ejection fraction should still be recognized as
having a high risk of sudden cardiac death. This is important
because these patients are not currently offered ICDs for the
primary prevention of sudden cardiac death, based on current
guidelines. Due to the low competing risk of death from
non-sudden causes, it is possible that these patients will
benefit from ICD implantation, but randomized trials are now
required. These issues are discussed in an accompanying editorial
from Dr. Markman of Johns Hopkins University, and Dr. Nazarian,
Hospital of University of Pennsylvania.


                               
The next study enhances our understanding of the role of immunity
in hypertension. Now, the innate antigen-presenting cells and
adaptive immune T-cells have long been implicated in the
development of hypertension, however, the T-lymphocytes subsets
involved in the pathophysiology of hypertension remain unclear. A
small subset of innate-like T-cells expressing the gamma-delta
T-cell receptor, rather than the more commonly expressed
alpha-beta T-cell receptor, could play a role, and these were the
focus in today's paper by first author Dr. Caillon, corresponding
author Dr. Schiffrin, and colleagues from Sir Mortimer B. Davis
Jewish General Hospital, McGill University, Montreal, Canada. In
experimental models, the authors showed than angiotensin-2
infusion increased gamma-delta T-cell numbers and activation in
the spleen of wall tite mice, as well as in increased the
systolic blood pressure, and decreased mesentric artery
endothelial function in wild type mice, but not in mice devoid of
gamma-delta T-cells, or in mice depleted of gamma-delta T-cells
by depleting antibody injections.


                               
Furthermore, angiotensin-2 induced T-cell activation in the
spleen and peri-vascular adipose tissue was blunted in null mice.
In humans, there was an association between systolic blood
pressure and gamma-delta T-cells. In summary, this is the first
in-vivo demonstration that gamma-delta T-cells, a subpopulation
of T-cells, play a fundamental role in the development of
hypertension and vascular damage. These results will help design
novel treatments to limit the progression of hypertension and
vascular damage.


                               
The final paper describes a novel multi-modality strategy for
cardiovascular risk assessment. Dr. de Lemos and colleagues from
UT Southwestern Medical Center in Dallas, Texas, hypothesized
that a strategy combining promising biomarkers across multiple
different testing modalities would improve global and
atherosclerotic cardiovascular disease risk assessments among
individuals without known cardiovascular disease. These
modalities included: left ventricular hypertrophy by
electrocardiogram, coronary artery calcium, N-terminal pro B-type
natriuretic peptide, high sensitivity cardiac troponin-T, and
high sensitivity C-reactive protein.


                               
Using data from 6,621 individuals of the multi-ethnic study of
atherosclerosis, or MESA, as well as 2,202 individuals from the
Dallas heart study, the authors evaluated the association of test
results with the global composite cardiovascular disease outcome,
and that would include cardiovascular death, myocardial
infarction, stroke, coronary or periphery revascularization,
incident heart failure or atrial fibrillation, as well as
atherosclerotic cardiovascular disease outcomes, which included
fatal or non-fatal myocardial infarction or stroke. Over more
than 10 years of follow-up, the authors found that each test
result was independently associated with the global composite
cardiovascular disease events in MESA. When the 5 tests were
added to a base model, the C statistic improved, that was
significant integrated discrimination improvement, and net
reclassification improvement, and the model was well-calibrated.
Using a simple integer score counting the number of abnormal
tests, they showed that global cardiovascular disease risk
increased with increasing score in a graded fashion. These
findings were replicated in the Dallas heart study, and were
similar for the atherosclerotic cardiovascular disease outcome.


                               
This study therefore supports the potential value of a
multi-modality testing strategy in selected individuals, in whom
additional risk stratification is desired, beyond measurement of
traditional atherosclerosis risk factors. The authors do
highlight that additional studies are needed to validate the
present findings, determine the optimal approach to
implementation, and address direct and indirect cost implications
of the additional testing.


                               
Well, that wraps it up for your summaries. Now for our feature
discussion.


                               
Our feature paper today tells us that a polygenic risk score
identifies a group of individuals with a higher burden of
atherosclerosis, and greater relative benefit from statin therapy
in the primary prevention setting. But perhaps even more
significant, is that it addresses the fact that even relatively
small effect sizes of common snips gathered together in a genetic
risk score may have clinical utility in the prediction of
cardiovascular disease, and to discuss this I'm so pleased to
have the first author, Dr. Pradeep Natarajan from Massachusetts
General Hospital, and Dr. Anand Rohatgi, associate editor from UT
Southwestern. Welcome, gentlemen.


Dr. Pradeep Natarajan:  Thank you very much, Carolyn.


Dr. Anand
Rohatgi:         
Thank you, Carolyn.


Dr. Carolyn
Lam:              
Pradeep, could you start by telling us what you did? This was a
tour de force, please.


Dr. Pradeep Natarajan:  Yeah, thanks so much for the
invitation and the enthusiasm. So, briefly, large-scale,
genome-wide association studies have discovered genetic risk
variants in the population that individually associate with
coronary disease risk. Many others have shown that an aggregate
of these genetic risk variants predisposes to an increased risk
for coronary disease by about 60%. But we sought to, with this
study, understand how primary preventive statins could influence
that risk, and whether these insights could be helpful in
refining statin eligibility. So, among the individual variants
that had been associated with coronary disease, we developed a
risk score. This encapsulated 57 individual genetic variants.
This risk score is independent of traditional cardiovascular risk
factors, and identified individuals with a greater burden of
sub-clinical atherosclerosis, defined as coronary artery calcium
and carotid plaque, and two observational cohorts in individuals
with a greater absolute and relative benefit from statin therapy
from a subgroup analysis within the WOSCOPS clinical trial.


                               
What we were surprised by is that the conventional wisdom, that
all previously described subgroups within statin trials had the
same relative benefit, and statins per unit of alveol cholesterol
lowering. So, about 20 to 25% lowering of risk per 40mg per
deciliter of alveol cholesterol. So we clinically identify
individuals who just start out at high absolute risk, assume that
the relative benefit will be the same across everyone, and
optimize the number needed to treat simply by just finding
individuals at high risk. But, here we didn't see the expected 20
to 25% lowering in the high genetic risk group, we saw actually a
44% relative risk reduction for the same lowering of alveol
cholesterol. And we have now observed that across three different
clinical trials, and these individuals are at high baseline risk,
so this translates into an even more optimized number needed to
treat, and really the opportunity to identify individuals earlier
with an age independent biomarker.


Dr. Carolyn
Lam:              
That's really cool, in fact, the number needed to treat in the
high-risk score group was impressively low at 13.


Dr. Pradeep Natarajan:  That's correct. Now, overall in the
WOSCOPS trial, if you look at all individuals, it's about 38, so
it is a high risk primary preventive group of men with, you know,
substantial hyperlipidemia, but if you look at at least a
relative difference between the two, going from 38 to 13, that's
about a three-fold improvement of the number needed to treat.


Dr. Carolyn
Lam:              
You know, what you said about it not correlating with exactly
what you expected with the drop in LDL and so on, does that mean
that this genetic risk score, that a lot of the snips are
probably associated with LDL levels, but that a lot of them may
be giving more information beyond LDL? Is that what it means?


Dr. Pradeep Natarajan:  Yeah, you know, it's interesting.
Most of the genetic variants that are associated with coronary
disease actually do not seem to clearly influence traditional
cardiovascular risk factors. The latest best estimate of that is
about 39% of them associate with traditional cardiovascular risk
factors, and then a subset with LDL cholesterol. So the aggregate
score actually does not associate with traditional risk factors,
and including with LDL cholesterol.


Dr. Carolyn
Lam:              
Wow, and Anand, I'm sure we had so many discussions with the
editors about the paper. Could you share some thoughts?


Dr. Anand
Rohatgi:         
Yes, Carolyn. Circulation as a journal represents the best in
cardiovascular science, and we're always interested in the
highest-level articles related to atherosclerotic cardiovascular
disease. So, when we received this manuscript from Pradeep and
Sekar’s group, really leaders in the field, we were really
excited, and as we went through the review process we got even
more excited because it, as you said, Carolyn, it really was a
tour de force, it was a high-quality article and it combined
multiple things, and that's what we're really interested in
seeing at Circulation, is combining several aspects, in this case
genetics, sub-clinical atherosclerotic imaging, and also
treatment effect.


                               
And, you know, it's interesting because several recent
manuscripts looking at genetic risk scores, they were associated
with coronary disease but it wasn't clear that they were
improving what we call risk prediction performance indices, at
least enough to meet the bar of incorporating them into
guideline-type recommendations. So I think the field wasn't sure
how to move forwards with this type of information, but now I
think this study really demonstrates that this type of risk
score, this genetic risk score, really can inform treatment
decisions in a big way. And so we were really excited to talk
about that and then see it move forward.


Dr. Carolyn
Lam:              
So a question for both of you now. Can these data be extrapolated
to other cohorts of patients? I mean, WOSCOPS was predominantly
white, and all were males, right? So, Pradeep, would you like to
take that first?


Dr. Pradeep Natarajan:  That's an excellent observation, and
I think ... A clear limitation in the field, but an outstanding
question that I think can be addressed going forwards. So, the
main challenge is that the epidemiological cohorts that were used
for genetic analysis largely have been of European ancestry, and
we know that genetic background and a variety of non-genetic
factors influence cardiovascular disease risk, so in genetic
analysis of European individuals the influencers of coronary
disease risk may not influence cardiovascular disease the same in
non-European ethnicities. And, you know, we've done some work of
this specifically in African-Americans, and there are some
differences. You know, African-Americans are largely mixed of
both African and European ancestry, some of that seems to also
influence how you interpret the cardiovascular genetic risk
score.


                               
Ideally you would have a risk score that is not influenced by the
genetic background, and so the next step going forward are one to
look to see how well this risk score predicts in non-European
ancestry, because, obviously, not as much statin clinical trial
information in non-European cohorts, but I think looking at the
treatment effect in non-Europeans will be important. And then,
you know, the third step is we and others are participating in
several now large ongoing efforts to really define what the
genetic influences are in non-European ancestries, and I think
that will be a very important next step that's really critical
before the clinical implementation.


Dr. Carolyn
Lam:              
Yeah, talking to you from Asia, that's music to my ears,
obviously. Anand, did you have any questions for Pradeep or
anything else to add about the paper?


Dr. Anand
Rohatgi:         
Yeah, I wanted to add one or two comments. One thing that this
study demonstrates is that the genetic risk scores, whether they
relate to traditional risk factors or lipids, that doesn't
necessarily translate to what it might mean in terms of treatment
benefit, and so I think that concept is generalizable and now it
needs to be tested in other ethnicities, other types of
subgroups, but I think you can disentangle a relationship with
risk factors and lipids to its treatment effect and this study
really nicely shows that.


                               
And I think just to take a step back, we know statins work in
intermediate-risk patients, maybe even low-risk patients with the
most recent studies, but at a public policy level, and just as a
cognition, we really want to narrow the focus, it's something
called precision medicine that the American Heart Association is
promoting as a concept, and I think that this study really
demonstrates that here we have now another tool that can reduce
this number needed to treat, make this choice for statins more
precise, maximizing the benefits and limiting cost. So, I think
that concept is very generalizable, it needs to be tested now in
multiple populations, like Pradeep said, and I guess one of the
questions I had had for the authors is: how do we incorporate
this finding that they saw with sub-clinical atherosclerosis,
which we thought was very fascinating among the editors at
Circulation, that now they're also linking with sub-clinical
atherosclerosis, is that something that the investigators think
needs to be pursued further? Would that be something that would
be used clinically as well?


Dr. Pradeep Natarajan:  I think there are lots of
opportunities for this going forward, you know, in prior work
we've done the genetic architecture for clinical coronary disease
is actually very similar to sub-clinical coronary disease, and
there are many influences for sub-clinical coronary disease, and
clinical coronary-disease, that are both genetic and
environmental, and the aggregate effect from the polygenic risk
on sub-clinical atherosclerosis suggests that it's obviously not
absolute and there are other factors that influence sub-clinical
atherosclerosis.


Dr. Carolyn
Lam:              
Well, listeners, you heard it right here. Thank you for joining
us this week, tell all your friends about it, and don't forget to
tune in again next week.