Circulation June 13, 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.


                                               
In our feature discussion today, we will be talking about
insights from the PROMISE Trial regarding the prognostic value of
non-invasive cardiovascular testing in patients with stable chest
pain. First, here's your summary of this week's journal.


                                               
The first paper reports novel findings on gene smoking
interactions in coronary heart disease. Co-corresponding authors
Dr. Salahin from the University of Pennsylvania and Dr. Riley
from Columbia University and colleagues used data on almost
61,000 coronary heart disease cases and more than 80,000 controls
to investigate effect modification by smoking behavior at
established coronary heart disease and smoking-related genetic
loci.


                                               
They found that the cardio-protective effects associated with
allelic variation at the A-D-A-M-T-S seven, or ADAMTS7 locus,
were attenuated by 60% in patients who smoked tobacco, compared
to those who did not smoke. Allelic variation in ADAMTS7
associated with reduced coronary heart disease risk, was
associated with reduced ADAMTS7 expression in human aortic
endothelial cells and lymphoblastoid cell lines.


                                               
Furthermore, exposure of human coronary artery smooth muscle
cells to cigarette smoke extract led to induction of ADAMTS7.
These human genomic data therefore provide new insights into
potential mechanisms of coronary heart disease in cigarette
smokers and suggests that inhibition of ADAMTS7 may be a novel
potential therapeutic strategy for coronary heart disease that
may have particular benefits in individuals who smoke cigarettes.
This is discussed in an editorial entitled Holy Smokes, an
Interaction, by Dr. Braxton Mitchell.


                                               
The next paper provides first evidence that genetic
over-expression of CD39 may offer ischemic cerebral protection.
CD39 is an ectoenzyme with a PYRase activity, which cleaves ATP
and ADP. CD39 is expressed on the surface of myeloid and vascular
endothelial cells where it dissipates the high local
concentrations of ATP and ADP, which would otherwise serve as
potent pro-inflammatory and pro-thrombotic signals.


                                               
In the current study from first author Dr. Bick, corresponding
author Dr. Pinsky from University of Michigan Medical Center and
colleagues, authors used a model of permanent middle cerebral
artery occlusion to show that CD39 expression reduced edema,
infarct volume, and inflammation with corresponding improvements
in neurological outcomes, compared to control mice.
Over-expression of CD39 in only the myeloid cells also reduced
cerebral infarct volume. Thus, amplification of endogenous CD39
expression, or even administration of exogenous circulating CD39,
may be of future interest as a therapeutic target to minimize
ischemic injury caused by cerebral ischemia.


                                               
The next paper provides pre-clinical data to show that MicroRNA93
may have a therapeutic role in peripheral artery disease. First
author Dr. Ganta, corresponding author Dr. Annicks and colleagues
from University of Virginia, used MicroRNA-106b-93-25 cluster
knockout mice and showed that MicroRNA93 over-expression alone
was sufficient to enhance angiogenesis, arteriogenesis, and
perfusion in ischemic muscle via increased M2-like macrophages.


                                               
MicroRNA93 targeted interferon regulatory factor 9 to inhibit
immune response gene 1, and itaconic acid generation in
macrophages to induce M2-like macrophage polarization.
Furthermore, MicroRNA93 over-expression produced a paracrine
effect on macrophages that induced angiogenesis and skeletal
muscle recovery under hypoxic conditions in vitro.


                                               
Thus, these data demonstrate that MicroRNA93 induces beneficial
effects in multiple cells that can enhance perfusion in ischemic
limb and thus identifies MicroRNA93 as a putative therapeutic
target in clinical peripheral artery disease.


                                               
The next study is a large scale genetic analysis that represents
the most comprehensive causal assessment of adiposity with
cardiometabolic diseases to date. Co-corresponding authors Dr.
Cassis and Dale from University College London used 97 snips for
BMI, and 49 snips for waist-hip ratio adjusted for BMI, to
conduct mendelian randomization analysis in 14 prospective
studies supplemented with coronary heart disease data from
CADRIoGRAM+C4D, stroke data from METASTROKE, Type II Diabetes
data from DIAGRAM and lipids data from GLGC Consortium.


                                               
They found that both waist-hip ratio adjusted for BMI, and BMI
had causal effects on coronary heart disease and Type II
Diabetes, and were associated with higher left ventricular
hypertrophy, glycemic traits, interleukin 6 and circulating
lipids. However, only waist-hip ratio adjusted for BMI increased
the risk of ischemic stroke. Thus, both the amount of adiposity
and its distribution play important roles in influencing multiple
cardiometabolic traits and the development of cardiometabolic
disease.


                                               
Furthermore, the findings indicate that body fat distribution has
multiple roles in disease that are independent of general
adiposity. This suggests that physicians should pay attention to
measures of adiposity beyond BMI.


                                               
The next study addresses the conundrum that clinical trials show
benefit of lowering systolic blood pressure in people aged 80
years and above, but yet, non-randomized epidemiologic studies
suggest lower systolic blood pressure is associated with higher
mortality. In the current study by Dr. Ravindrarajah and
colleagues of King's College London, a population based cohort
study was conducted using electronic health records of 144,403
participants aged 80 years and older, registered with family
practices in the United Kingdom, and followed for five years.


                                               
Mortality rates increased with frailty level, and were highest at
a systolic blood pressure of less than 110 millimeters mercury.
Furthermore, systolic blood pressure trajectories showed an
accelerated decline in the last two years of life, without
evidence of intensification of anti-hypertensive therapy.


                                               
Thus, a terminal decline of systolic blood pressure in the final
two years of life suggests that non-randomized epidemiological
associations of systolic blood pressure with higher mortality may
be accounted for by reverse causation. That is, participants with
lower blood pressure values were closer on average to the end of
life. This is discussed in an accompanying editorial by Dr.
Naveed Sattar.


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


                                               
The evaluation of stable patients presenting with suspected
coronary artery disease is by far one of the most common
diagnostic evaluation strategies that we need to undertake in
cardiovascular medicine. There's a whole host of evidence
supporting prognostication based on various non-invasive tests,
such as anatomic imaging with coronary computed tomography
angiography, but also with stress testing, or functional testing,
such as stress nuclear or echocardiography, or exercise
electrocardiography.


                                               
However, our paper today really sheds light on the comparison of
these two strategies. And I'm just delighted to have starts with
me. First, the primary author of the paper, from the PROMISE
Trial, Dr. Udo Hoffmann, from Massachusetts General Hospital,
Harvard Medical School, and the editorialist of a beautiful
accompanying editorial, Dr. Leslee Shaw from Emory University
School of Medicine, Atlanta, Georgia.


                                               
Welcome both.


Dr.  Udo Hoffmann:       
Hi, Carolyn. Hi, Leslee.


Dr. Leslee
Shaw:              
Hi, Udo, how are you?


Dr. Carolyn
Lam:              
So, Udo, could you start by just sharing what you did in this
PROMISE Trial?


Dr. Udo
Hoffmann:         
The Promise Trial is a large comparative effectiveness trial that
was done between 2009 and 2012, with follow-up ending 2013, at
[inaudible 00:10:13] sites across the U.S. and Canada. And what
it did was compare two strategies for testing patients with
suspicion of coronary disease, symptomatic patients. These
patients were randomized to either receive a functional test
first, or an atomic test first, and the idea was to see whether
providing the functional information or the anatomic information
leads to differences in outcomes of these patients.


                                               
As you know, the primary paper showed that the health outcomes of
these two strategies were similar and not different. Now in this
paper here, we took the slightly different approach and we really
wanted to see how the results of the tests as they were seen by
the [inside 00:11:02] so it was all based on the sight
interpretations of these tests. How the results of these tests
actually were associated, or were associated with the health
outcomes. And so we directly compared categories of CT results,
and categories of functional testing results, and how they are
related to outcomes. The good news I think is that sight
interpretations in real life do actually have prognostic value
for both the anatomic or the CT, and also the functional testing,
and so findings as significant disease [inaudible 00:11:36]
ischemia have in fact similar prognostic value. And we also saw
that on the lower end of the findings, so mildly abnormal
findings for example, that the ability to see nonobstructive CAD,
perhaps if you're a difference maker and identify from additional
patients or group of patients that is at risk for [inaudible
00:12:01].


Dr. Leslee
Shaw:              
I think that often times we struggle with negative trial results,
if I can put PROMISE in that negative trial results. And here we
have a paper that I think really applies clinically. I think it's
going to have far-reaching clinical implications. I think if you
look at the CTA findings, this is a real world practice. I think
there's a simplicity to CTA interpretations that really is
amplified in the nice ability to risk stratify. Whereas the
functional interpretation, as you both know, is complex. It
integrates a lot of factors, wall motion, perfusion imaging, ST
segment changes, exertional symptoms, all of that, and I think we
see a lot of sight variability in that image interpretation on
the ischemia-side of the functional testing arm.


                                               
But there's and important finding from this paper, which I think
we have seen in bits and pieces prior to this report, and that is
that on the CTA side, you had about a third of the patients
having pure normal coronaries. So you see that very low risk in
that population. But what you see on the functional testing arm
is that the event rate in patients with normal studies and in
patients with a mildly abnormal study, the event rates were
identical, which is fascinating.


                                               
And importantly, two thirds of the population on the functional
testing arm were in those normal and mildly abnormal subgroups,
something like that. And that has important implications for what
is in that one third on a CTA side with normal findings versus
three quarters? Well I think from this randomized trial, I think
we can infer that you're going to have some non-obstructive
disease in that population, but you're also going to have
non-ischemic obstructive disease.


                                               
We know from FFR and all of the angiographic literature that not
every obstructive lesion is ischemic. And so on the stress
testing side, we have a lot of obstructive disease that
potentially is missed. And I think this study really clearly
illustrates that limitation of stress testing and it reflects
sight variability in imaging and the interpretation. It reflects
the patient populations and the struggles with doing stress
testing, but also just flat out reflects the ischemic cascade,
and what we can expect from an obstructive lesion, or a
non-obstructive lesion, that may not elicit ischemia.


                                               
So to that extent, I think Udo's paper is just, just far-reaching
and really clearly one of the most advanced papers that we have
seen in such a long time. From really providing an important
message for those imagers and for folks doing stress testing in
this country.


Dr. Carolyn
Lam:              
should we then always do anatomic testing first before selective
stress testing?


Dr. Udo
Hoffmann:         
The choice of testing is very much I think tied to the population
of the patient you're talking about. I think when you follow the
literature, 30 years ago when all the classic studies out of
[experienced centers 00:18:53] such as Cedar Sinai, were
published, the ischemia burden was much higher in the tested
population. Back then you had probably a third or 40% of patients
who in fact had some abnormality or ischemia on stress testing.
One of the findings here in this study, and that is true for both
tests, is that the prevalence of severe findings, severe
abnormalities, whether ischemia or obstructive disease, is what I
found testing is pretty similar, so it's both around 12%, but it
is relatively infrequent. And I think that has changed.


                                               
And you cannot expect, as Leslee pointed out nicely, it is not
expected from a stress test to detect non-obstructive disease
that has prognostic value, but doesn't necessarily explain these
symptoms that the patient is presenting. So we should not forget
that these patients do not come for primarily for prognostic
assessment, they come because they're symptomatic. And the
primary question is do we find an equivalent that could explain
the symptoms of the patient? And only once we are convinced that
there's no such equivalent that would for example lead us to
further assess the patient for potential reverse [inaudible
00:20:19] therapy, then the second question that can be answered
is for the prognostic implication of the test. And I think in
this relatively low risk population, this prognostic aspect gains
more importance irrelative to the diagnostic aspect.


Dr. Carolyn
Lam:              
I think Leslee made it very clear in her editorial as well, not
to forget in essence at the extremes of disease, that both tests,
both strategies conveyed similar prognostic information, and it
was more for the fine grain teasing apart that perhaps we need to
consider very, very carefully what your paper is saying. But at
the end of the day, it's about treating the patients for their
cardiovascular risk management, isn't it? Recognizing that even
if you don't have ischemia, if you've got the risk factors, like
you nicely showed, that we should be treating them for the risk
factors.


                                               
Leslee, want to share some of your thoughts there? You covered
that so nicely in your editorial.


Dr. Leslee
Shaw:              
Well I think that's one thing we've seen from PROMISE,
SCOT-HEART, and many, many other recent trials as of late, over
the last three or four years, is that the stress test is an
opportunity not only to assess ischemic burden, or that CTA's not
only a test to assess the extent and severity of coronary disease
as well as plaque, but it's an opportunity to identify clear,
preventive strategies for the patients.


                                               
And this is really something that I don't think at least
historically within the stress testing community, that we have
taken upon ourselves in order to say, "Okay, here we have a
symptomatic patient. We not only are going to assess ischemia,
but we're going to look at what else they need to do in order for
us to guide prevention." I think this is a clear reminder that
this is a great opportunity for us to have a bit of a paradigm
shift on the diagnostic testing, to take that whole picture if
you will of the patient, and really to focus in on prevention
because that is a great opportunity, as Udo talked about just a
few minutes ago, it's a great opportunity for us to set the
patient on the correct course.


                                               
The guidelines, as both of you know, focus in on having that
diagnostic evaluation and to implement guideline directed medical
therapy as a front line examination. This is a great opportunity
for us to just use that diagnostic evaluation ad the initiation
of appropriate care for the patient, and then to look at symptom
burden, recurrent symptoms, the need for additional
interventions. But that first step is guideline directed medical
therapy for the patient.


Dr. Udo
Hoffmann:         
Continuing on Leslee's excellent point, I think the paper I think
is hopefully a starting point to think about randomized trial,
because we assume some maybe come to the conclusion, okay, if you
have non-obstructive disease, you should be treated with
[inaudible 00:23:13] and aspirin. But we don't know that. I think
this is really a call for randomized trial. PROMISE was the one,
and it was a good trial. It looked at the association of strategy
with an outcome. I think one trial that is needed is to look what
specific therapeutic decisions based on imaging or based on test
diagnostic test findings, would be justified and would
potentially lead to improved outcomes. And that is true for both
the stress testing and the CT side. So I think this paper shows
the opportunities, but I don't think we have the randomized data
to exactly define what are the management options for each of
these details of the information that these test results deliver
us.


Dr. Carolyn
Lam: