Circulation October 23, 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. The ORBITA
Trial of percutaneous coronary intervention and stable single
vessel coronary artery disease has to be one of the most hotly
discussed in the cardiology world. The featured paper of this
week adds important knowledge that will help us understand the
physiology stratified results of ORBITA.


                                               
Coming right up after these summaries.


                                               
The first original paper this week provides novel mechanistic
insights that may lead to a new treatment approach for obesity
and hypertriglyceridemia. Co-corresponding authors, Drs Xiang and
Xia from Central South University of Xiangya in China, looked at
Reticulin 3, which is an endoplasmic reticular protein that has
previously shown to play a role in neurodegenerative diseases.


                                               
In the current paper, the authors show that over-expression of
Reticulin 3 in mice induced obesity and a greater accumulation of
triglycerides. Remarkably, increased Reticulin 3 expression was
also found in patients with obesity and hypertriglyceridemia.
They further showed that Reticulin 3 played critical roles in
regulating the biosynthesis and storage of triglycerides and in
controlling lipid droplet expansion. Thus, these results suggest
that inhibiting the expression of Reticulin 3 in fat tissue may
be a novel therapeutic approach to treat obesity and
hypertriglyceridemia in the future.


                                               
The next study provides insights into the genetic determinates of
residual cardiovascular risk in patients already receiving
statins. First author Dr Wei, corresponding Dr Denny from
Vanderbilt University Medical Center and their colleagues
performed a genome-wide association study and identified that a
variation at the LPA Locus was associated with coronary heart
disease events during statin therapy and independent of the
extent of LDL cholesterol lowering. The association of the LPA
Locus with coronary heart disease events persisted in individuals
with an LDL cholesterol less than 70 milligrams per deciliter.
These findings, therefore, provide support for exploring
strategies targeting circulating concentrations of lipoprotein(a)
to reduce coronary heart disease events in patients already
receiving statins.


                                               
The next paper provides important mechanistic results that help
us understand pathways in atherosclerotic plague regression. Co
first authors, Drs Mueller and Zhu, corresponding author Dr Fazio
from Oregon Health and Science University and their colleagues
have previously shown that mice lacking an LDL receptor with beta
protein 1 in macrophages undergo accelerated atherosclerotic
plague formation. However, in the current study they sought to
explore the role of macrophage LDL receptor protein 1 during
plague regression. They did this by placing EPO E deficient mice
on a high fat diet for 12 weeks, then reconstituting their bone
marrow using wall type or macrophage LDL receptor protein 1
deficient mice as donors, and finally switching them back to a
chow diet for 10 weeks. The authors found that the lack of LDL
receptor protein 1 expression in macrophages unexpectedly caused
more atherosclerosis regression. Mice with macrophages lacking
LDL receptor protein 1 showed less M1 macrophages in the plague
and increased CCR7 dependent egress of macrophages from the
plague. Thus, loss of macrophage LDL receptor protein 1 has a
dual and opposite effect on plague biogenesis, depending on
whether the plague is growing or shrinking.


                                               
The next paper highlights the intercalated disc, which is a
specialized intercellular junction, coupling cardiomyocyte
electrical activity in forced transmission as a mechanosensitive
signaling hub for causative mutations in cardiomyopathy. First
author Dr Trembley, corresponding author Dr Small from University
of Rochester School of Medicine and Dentistry and their
colleagues showed that myocardin related transcription factors
associated with desmosome proteins of their intercalated disc in
both murine and human hearts. Genetic deletion of myocardin
related transcription factors in cardiomyocytes led to rapid
onset of dilated cardiomyopathy in response to pressure overload
hypertrophy. Furthermore, myocardin related transcription factors
were required for the maintenance of sacromere and intercalated
disc integrity under pathological stress. These findings,
therefore, provide a unique link between the intercalated disc
and mechanosensitive transcriptional regulations. Since myocardin
related transcription factors redistribute from intercalated disc
in human heart failure, this may represent a novel signaling
complex present in cardiomyopathic characterized by desmosome
dysfunction.


                                               
The next paper investigated the association of blood pressure
with peripheral arterial disease events, using data from the
ALLHAT Trial. Co first authors Drs Itoga and Tawfik,
corresponding author Dr Chang from Stanford University School of
Medicine and their colleagues found that both lower systolic
blood pressure of less than 120 and higher systolic blood
pressure of above 160 millimeters of mercury were both associated
with higher rates of peripheral arterial disease events.
Diastolic blood pressure less than 70 and a pulse pressure above
65 millimeters mercury were also associated with increased rates
of lower extremity peripheral arterial disease events. Given that
the recent revised blood pressure guidelines advocate lower
systolic blood pressure targets for overall cardiovascular risk
reduction, the authors called for future, further refinement of
optimal blood pressure targets, specific for peripheral artery
disease.


                                               
The final original paper this week provides the first integrated
atherosclerotic disease risk calculator to incorporate risk
factors including high sensitivity C reactive protein, family
history, and coronary artery calcium data. First and
corresponding author Dr Khera from UT Southwestern Medical Center
and colleagues used 3 population-based cohorts to develop Cox
Proportional Hazards Models for the outcome of atherosclerotic
cardiovascular disease. The derived Astro-CHARM model
incorporated factors like age, sex, systolic blood pressure,
total and HDL cholesterol, smoking, diabetes, hypertension
treatment, family history of myocardial infarction, high
sensitivity c reactive protein, and coronary artery calcium
scores. The model performance was validated externally in a 4th
cohort, and shown to improve risk prediction compared with
traditional risk factor equations, and showed good discrimination
in calibration in the validation cohort. A mobile application and
web based tool was developed to facilitate the clinical
application of this tool, and is available at www.astrocharm.org.


                                               
And that brings us to the end of this week's summaries. Now for
our featured discussion.


                                               
Gosh, I am learning for the first time today that it's terribly
inconvenient to lose my voice when I am a podcaster. This is
Carolyn Lam and our featured discussion that I am so excited
about, but the cool thing is the thing we are talking about is so
hot that you don't even need me to say anything. And what we are
talking about is the ORBITA Trial. That was greeted with as much
hype and hoopla and sensationalism since its publication in 2017.
I am so proud to have the first and corresponding author Dr Rasha
Al-Lamee from National Heart and Lung Institute Hammersmith
Hospital in London. I also have Dr Ajay Kirtane from Columbia
University Medical Center in New York Presbyterian Hospital and
the Cardiovascular Foundation in New York as the editorialist for
the paper. And finally, our associate editor Dr Manos Brilakis
from UT Southwestern. Rasha, why don't you just take it away and
just tell us, what is your paper focusing on in this week's
issue?


Dr Rasha
Al-Lamee:         The
paper that was published in this issue in circulation is
basically our second analysis of the ORBITA Trial, a substudy
analysis. Essentially, looking at the primary endpoint and the
secondary endpoints of ORBITA, and having a look at those
patients from ORBITA and seeing whether there was any association
between their invasive physiological assessment using FFR and ISR
at the pre-randomization stage and seeing whether the level of
ischemia on ISR or FSR was associated or predicted in the way in
which they performed in terms of their endpoints. To see whether
there was any difference in the placebo control efficacy of
angioplasty in those patients who have more or less severe
ischemia on their invasive physiological assessment.


Dr Manos
Brilakis:           
First off, that's a phenomenal paper, and I think she puts things
into perspective. I know Ajay put an excellent tutorial. I think
all of us were surprised about the findings. You would expect
that the more ischemia, that you might see a little more
response. Any thoughts as to why there wasn't such an
association?


Dr Rasha
Al-Lamee:         I think
it's so difficult because, of course, as we all know from the
primary paper that was published in The Lancet, in terms of the
primary endpoint, which would be change in exercise time and the
difference between the two groups, the difference is actually
much smaller than we expected. And when we have such a small
difference in exercise time, the ability to be powered enough to
be able to split that endpoint based on stratification of
invasive physiology becomes very difficult, and we're perhaps
underpowered to be able to do that.


                                               
Where we did see a very great effect in terms of the primary
assessment in The Lancet paper was in stress echo ischemia. What
we saw is those patients who had angioplasty were far more likely
to have an improvement, or indeed, a normalization of their
ischemia on their stress echo. Where we saw a big difference the
two groups we were then clearly powered to be able to stratify
those patients based on their invasive physiology, and for that
secondary endpoint we saw that, in fact, tied to your stenosis or
the lower your ISR or FRR, the more likely you are to have an
improvement in stress echo, having had placebo controlled
angioplasty.


Dr Manos
Brilakis:           
Ajay, I know you had a lot of things insight into the vision of
the tutorial for the ORBITA Trial. What are your thoughts about
the findings?


Dr Ajay
Kirtane:                
I would, first of all, congratulate Rasha and the ORBITA team,
there are others, for not only doing the main trial, but for
conducting these detailed analyses, which were clearly set up
ahead of time, and that's been one of the critiques of the trial
is why were patients with normal-ish range FFRs included. Well,
part of it was to test this hypothesis, and perhaps to show that
there would be a correlation between the change in the FFR, if
you will, and the endpoints that were measured.


                                               
So, I think that that's the first part, that this is actually a
scientific experiment, and a thoughtful one in doing so. I think
exactly as Rasha said though, if there is a limited signal, with
respect to the overall trial, then further subsetting is less
likely to show a significant signal. I think that's exactly what
the investigators found. The only other comment I would make
though is, I would commend Rasha and the team for producing other
analyses that are novel in this manuscript including the freedom
from angina analysis, as well as responding to some of the
earlier critiques of the trial and not using specific
methodologies to adjust the baseline differences improves. Those
are also included in this analysis.


Dr Manos
Brilakis:           
Yeah, absolutely, I think that was very enlightening to see, the
freedom of angina. And I know there was some questions whether
that might change the overall findings from the studies, so there
is some quality of life benefit. Rasha, what is your thoughts
about this? I mean, you must understand this study better than
anyone else. People who have stable angina, should they undergo
PCI or not?


Dr Rasha
Al-Lamee:         I think
the freedom from angina signal was very important, and obviously
not something that we had pre-specified, so it wasn't reported in
the primary analysis. We're obviously much more able now, since
we've published that primary analysis to do secondary analyses
and look at things that perhaps we haven't pre specified. And
it's interesting to see that 20% more patients are free from
angina having had angioplasty vs. placebo. Having said that, to
me, it's a fantastic finding, but still a little unexpected. Much
less than we might expect looking at unblinded data, or our
unblinded clinical experience. I would have expected much higher
levels from freedom of angina.


Dr Rasha
Al-Lamee:         I think
what we know, and what we've seen both from this paper, very
importantly, and also the primary manuscript, is that the
efficacy of angioplasty is very tightly linked to the improvement
in ischemia. We've actually, in fact, got more papers that are
coming out from our group recently. And that you can predictably
tell your patients that if I sense a lesion that's causing a
reduction in ISR or FFR, and potentially symptoms, then I will
improve your ischemic burden.


                                               
What I think is more tricky is how much I will relieve your
symptoms, or make you feel better. That may be because symptom
assessment itself is very tricky, and perhaps that actually just
diagnosing cardiac angina is actually a very difficult thing. The
easiest way to piece out improvement in symptoms is to find those
patients who become free of angina because, of course, that's the
binary end point. When we look at grades of symptoms, and whether
their angina frequency improves, or whether the level of angina
improves in terms of PCI, then I think it becomes much harder,
especially in a blinded trial where, of course, when people come
back, even with atypical chest pain, it will still be recorded as
potentially angina because, of course, both the investigators and
the patients have no idea what they've had done, which is quite
different from real life where, of course, you are able to think
more about whether this chest pain might indeed be from the heart
or from other causes.


Dr Manos
Brilakis:           
Perfect, thank you very much. And I would completely agree with
you that, the study was perfect. And, as Ajay said, it is
something that we needed, and more of them should be done. And I
think you are right that this is the best way to piece out the
symptom improvement.


                                               
Ajay, any final comments?


Dr Ajay
Kirtane:                
I think that the toughest challenge with trials like this is to
really enroll the patients that many of us as interventionists
feel would really improve in terms of their symptom class. Even
despite these efforts, if one looks at the baseline of anginal
frequency in the trial, the means are relatively high, which
suggest that the anginal burden, at least in terms of
measurements through the anginal questionnaire is not that
severe. One could argue that somebody has severe angina that is
occurring all the time, that those are types of patients that are
hard to randomize in a clinical trial.


                                               
I think, at least my overview stepping back perspective of the
context of ORBITA within clinical practice, is exactly that. The
trial is an important scientific advance, but this does not
encompass the answer for every single patient that comes to see
us in the office that have a range of symptoms, very severe to
less severe. That was something Rasha has been saying all along
as well. It's not something that we could over extrapolate this
to every patient that we see. So, I think that when the hype dies
down, these types of scientific analyses will stand out. They
emphasize the need for regular clinical research, and in that
way, I think has generated a lot of attention not only to the
clinical field here, but also the scientific pursuit of evidence.
That's a really magical thing.


Dr Rasha
Al-Lamee:         I
think, if I can add to that Ajay, I think it's probably also sort
of the assessment of symptoms is incredibly important. I think
many of us, and I'll include myself in this, when we see a very
tight stenosis, are happy to essentially correlate any level of
symptoms to that tight stenosis. One thing I've learned from all
this, I want to see reproducible angina that very much is
textbook, cardiac caused chest pain, and the atypical anginas we
see, perhaps some of that pain is not from that stenosis, but
from somewhere else. Therefore, by fixing that stenosis, we don't
necessarily make that pain go away.


Dr Manos
Brilakis:           
Absolutely, and I think you are absolutely, if it is something
simple vessel disease, if it's something a little more
straightforward, then I think you are right Ajay, that this is
much harder, multiple vessel disease especially in people with
reduced ejection fraction.


Dr Carolyn
Lam:               
You've been listening to Circulation on the Run! Don't forget to
tune in again next week!