Circulation May 05, 2020 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.


Dr Greg Hundley: And I'm Greg Hundley, associate editor from the
Pauley Heart Center at VCU health in Richmond, Virginia. Well
Carolyn, our feature this week really examines long-term efficacy
of drug eluting stents versus coronary artery bypass grafting in
those patients with left main disease. Really looking at
long-term extended follow up from the PRECOMBAT trial but before
we get to that, how about we grab a cup of coffee and jump into
some of the other articles in the issue? And I'll start off. My
first article is a basic science paper looking at catecholamine
sensitive and ventricular tachycardia in ARVC. And it comes from
Dr Long-Sheng Song from the University of Iowa Carver College of
Medicine.


So, the study from Dr Song used protein mass spectrometry
analyses and that identified integrin beta one is downregulated
in those patients with arrhythmogenic right ventricular
cardiomyopathy hearts without changes to calcium handling
proteins as adult cardiomyocytes express only the beta-1 D
isoform, they generated a cardiac specific beta-1 D knockout
mouse model and perform functional imaging and biochemical
analyses to determine the consequences from integrin beta-1 D
loss of function in hearts in vivo and in vitro.


Dr Carolyn Lam: Nice, very elegant design. So what were the
results Greg?


Dr Greg Hundley: Well Carolyn, the authors found that integrin
beta- 1D deficiency and RyR2 serine 2030 hyper phosphorylation
were detected by Western blotting in left ventricular tissues
from patients with ARVC but not in patients with ischemic or
hypertrophic cardiomyopathy. And in the mouse experiments, beta-1
D negative or knockout mice exhibited normal cardiac function and
morphology, but presented with catacholamines sensitive
polymorphic ventricular tachycardia consistent with increased
RyR2 serine 2030 phosphorylation and apparent calcium handling in
beta-1 D knockout cardiomyocytes.


So Carolyn, in conclusion, the authors found their data suggest
that integrin beta-1D deficiency represents a novel mechanism
underlying the increased risk of ventricular arrhythmias in
patients with ARVC.


Dr Carolyn Lam: Okay. You told us about integrin beta-1 D and I'm
going to tell you about apolipoprotein M. So Greg, what do you
know about apolipoprotein M?


Dr Greg Hundley: Well, Carolyn, at seven o'clock the morning, I
seem to have forgotten a little bit about that. Can you remind me
what apolipoprotein M is?


Dr Carolyn Lam: Sure Greg, very happy to. So apolipoprotein M or
apoM mediates the physical interaction between high density
lipoprotein particles and sphingosine 1-phosphate and exerts an
anti-inflammatory and cardio-protective effects in animal models.
Now listen on, listen on. So authors, Dr Chirinos from Perelman
Center for Advanced Medicine, University of Pennsylvania and Dr
Javaheri from Washington University School of Medicine and
co-authors hypothesized that reduced levels of apoM would be
associated with worse outcomes in human heart failure.


Specifically, they tested the hypothesis that reduced circulating
apoM would be associated with the risk of death, a composite of
death, ventricular assist, device implantation or heart
transplantation and a composite of death, heart failure related
hospitalization among adults with heart failure and rolled in a
large multicenter Penn heart failure study. They did stratified
analysis in patients with heart failure with reduced and
preserved ejection fraction and even replicated these findings in
two independent cohorts, the Washington University heart failure
registry and a subset of the TOPCAT trial. What they found was
that reduced apoM plasma protein levels indeed were associated
with adverse outcomes in heart failure including both HFpF and
HFrF. The relationship between reduced apoM and outcomes and
heart failure was particularly pronounced when concentrations of
its binding partner sphingosine 1-phosphate were also reduced.
ApoM protein levels were associated with inflammation in human
heart failure and thus the conclusion being that apoM represents
a risk marker in human heart failure.


Further studies are of course needed to assess whether it could
be a therapeutic target as well.


Dr Greg Hundley: Very good. Carolyn. So more information for the
world of heart failure isn't it. I'm going to sort of switch over
to coronary artery disease and talk about low attenuation
non-calcified plaques that are sometimes appreciated on cardiac
computed tomography scans. And in this study, Dr Michelle
Williams from the University of Edinburg evaluated the results
from the multi-center SCOT-HEART trial or the Scottish computed
tomography of the heart. So Carolyn, the future risk of
myocardial infarction is commonly assessed using cardiovascular
risk scores, coronary artery calcium score or coronary artery
stenosis severity and the authors assessed in 1,769 patients
about 56% men and the average age 58 years and they followed them
up for a median of 4.7 years and looked at whether noncalcified
low attenuation plaque burden on coronary CT angiography might be
a better predictor of the future risk of myocardial infarction.


Dr Carolyn Lam: Interesting. So what did they find?


Dr Greg Hundley: Well, low attenuation plaque burden was the
strongest predictor of myocardial infarction irrespective of
cardiovascular risk score, coronary artery calcium score or
coronary artery area stenosis. And patients with low attenuation
plaque burden greater than 4% were nearly five times more likely
to have subsequent myocardial infarction and the hazard ratio was
4.65 with a confidence interval of two to more than 10 and a
half. So in conclusion, Carolyn in patients presenting with
stable chest pain, low attenuation plaque burden is the strongest
predictor of fatal or nonfatal myocardial infarction and these
findings may add to classical risk predictors of myocardial
infarction.


Dr Carolyn Lam: Wow. Important findings. Okay, let's go onto what
else is in this week's journal issue. There's an online mind by
Dr Jaffe. It's on the universal definition of myocardial
infarction. It talks about both present and future
considerations. There's an ECG challenge by Dr Arias and what's
described as spontaneous wide QRS complex rhythm in a patient
with wide QRS complex tachycardia.


Dr Greg Hundley: Very good, Carolyn. Well, I've got two other
articles. Another on my mind piece from Professor Peter Nagele
from the University of Chicago Medicine and it discusses a
simplified proposal to redefine acute MI versus acute myocardial
injury. Looking at that troponin question. And then finally Dr
Fabian Hoffman from the Heart Center and University of Cologne
has a research letter on providing new data regarding the
evolution of pulmonary hypertension during severe sustained
hypoxia.


Well Carolyn, how about we get onto that feature discussion
looking at left main disease and whether we should place an
intercoronary stent or undergo coronary artery bypass grafting.


Dr Carolyn Lam: Important question. Let's go, Greg.


Dr Greg Hundley: Welcome everyone to our feature discussion today
that really pertains to interventional cardiology and we're very
fortunate to have Duk-Woo Park from Asian Medical Center in
Seoul, South Korea and our own associate editor, Dr Manos
Brilakis from the Minneapolis Heart Institute. Well Duk-Woo, we'd
like to get started with you and could you tell us a little bit
about the background data and the hypothesis related to your
research study?


Dr Duk-Woo Park: Our research, it was the 10-year report of the
PRECOMBAT trial. If I'm going to first introduce the background
over the last half of a century bypass surgery, it was a
mainstream, the number one choice of on protecting the main
disease. Yeah. Did you know unprotected left main disease, the
one were very high risk of coronary artery disease and owing two
and the supply, the large burden of myocardium. But the last two
decades, 20 years. Their remarkable evolution in PCI field
including development adaption of a drug eluting stent and the
adaption of intravascular ultrasound as well as experience of
intervention or catalyst expertise. So on the basis of such
evolution, many interventional cardiologists think about that, a
PCI with a drug eluting stent. Will it be non-inferior to a
standard type A surgery? Sometime for single region PCI could be
very nice alternative option for unprotected left main disease
that the reason why we're going to start quick on the trial. This
trial already done 15 years ago at the time. We designed this
PRECOMBAT trial on the basis of that background.


Dr Greg Hundley: Very good. Well can you tell us a little bit
about the study population of this trial and what was your study
design?


Dr Duk-Woo Park: This is a open library trial design and we at
first time we evaluated the noble unprotected left main disease
and the for considerable for clinical and ethic eligibility,
initially assessed by intervention or cardiologists as you as a
cardiac surgeon and the reason why we try to pick up the post
treatment eligible population and then at the screening initial
re-screen the nearly 1,400 patient and then finally 600 of
patient who was our individuation one arm is drug eluting stent,
first-generation ciphers 10 versus another arm is convention or a
coronary artery bypass stent grafting.


Dr Greg Hundley: What were you looking for your outcome measures
and how long did you follow these patients?


Dr Duk-Woo Park: Initially and the BDN two year follow and are
published in England, the journal of medicine nearly eight years
ago. And then we did five year follow-up at the publish the JAG
in five years ago and the this time is a, we did complete that 10
year follow up all the render mutation population and the median
follow-up duration is nearly more than 11 years and we complete
10 year follow-up and the key outcome was PCI is a comparable
apart from surgery for treatment of left main disease.


Dr Greg Hundley: And were there other outcomes that you were
looking for?


Dr Duk-Woo Park: We evaluated several important clinical
outcomes. We primary end the point we select competent outcome
compass of all cause of mortality by myocardial infarction,
stroke, or ischemia-driven target vessel revascularization.
Secondary outcome was each component of a primary outcome
all-cause mortality as you raise the harder clinical and the
point like compost outcome like this am I sure. So finally we did
not any statistical difference with the regard to primary
composite outcome as well as a hard clinical compost outcome as
death or stroke. Finally, we did not detect all-cause mortality.
One exception or difference was a target vascularization as well
as a repeat rebase collateralization was a much higher after PCI
than after bypass surgery.


Dr Greg Hundley: So overall, in this more lengthy follow up of 10
years. The primary outcomes were similar between the two
interventional arms, but there was a difference in target vessel
revascularization. With that being more frequent after PCI as
compared to bypass, were there any other subgroups that tended to
have distinctions or discrepancies between your primary outcome?


Dr Duk-Woo Park: As the sensitive to analysis, in circulation we
supply the subgroup analysis or more, we did not find any
differential treatment. IPEC according to subgroup in age group,
diabetes and clean-cut presentation or in environmental coronary
embolism shock versus application. We didn't find any interaction
effect, just the except the extent of disease vessel, left or
main. We the three best three digit bypass surgery was better
than PCI. However we did not do any P value. Adjust them on. So
interpretation is should it be cautious.


Dr Greg Hundley: Well you know as an interventional cardiologist,
what new information does this bring and how do you interpret the
results of this study relative to other studies that have been
published in the past?


Dr Emmanouil Brilakis:  I think this is a very timely study,
especially since about a year ago we did have the five-year
outcomes from two other similar trials, the Excel file and the
Nobel trial which say randomized patients with unprotected left
main disease to either PCI or bypass. And actually those studies
had some differences which are also relevant to the present
study. So for example, Excel overall the outcomes were similar.
There was a higher all-cause mortality in the PCI where normal
had better outcomes in terms of death, MIT VR, but there was no
difference in mortality. So I think the natural question that
comes up from the studies was whether mortality is different with
PCI versus coronary bypass and you know the PRECOMBAT, the 10
years. It's really suiting in that respect because it doesn't
show any difference in the overall mortality. So I think this
comes very timely and the answers a lot of questions. Of course
there's limitations with the sample size and the number of
patients treated, but I think although it's a very timely result.


Dr Greg Hundley: Maybe I'll start first with you, Manos and then
I'll circle back to you. Duk-Woo. Manos what do you see is the
next important study to perform in this field?


Dr Emmanouil Brilakis:  I think the natural question here is
these outcomes which are similar but use first generation drug
eluting stents, which we no longer use. He did use high
proportion of five which is an excellent feature in, again
congratulate Duk-Woo and the other co-investigators for doing
such a high rate of follow-up. But we now know that the
techniques, for example, for bifurcations, maybe the DK crush or
double DK crush might be a better technique to do. So in my mind,
the next question would be if who use the current, a much
improved the drug eluting stent and state of the art bifurcation
techniques. For example, DK crush where the double-kiss crush
bifurcation would, the outcomes have been different and perhaps
PCI will be similar, even better than bypass in long-term
outcomes. So for me this next study will be state of the art
techniques, state of the art materials and long-term for
follow-up as in frequently.


Dr Greg Hundley: Duk-Woo. How about from your perspective?


Dr Duk-Woo Park: You know, a future perspective is a very
difficult to expect. Our trial is the longest to follow-up trial.
We have the nation are insurance support and we nearly a hundred
percent pop picked up fighters status, but I think most of them
interventional cardiologists as well as a cardiac surgeon. One
true additional longest follow-up Excel and Noble trial. The
reason why we didn't do additional random trial using additional
second generation drug eluting stent. We already do exit trial
approximately 2000 and noble trial and more than thousand
patients we already do and the two trial a complete five-year
follow and most of the trial is as well as the clinician want to
extend the follow-up of Excel and Noble trial but I don't know
how much that extended of a follow-up would be possible.


Dr Duk-Woo Park: The next step as you know the intervention or
cardiac surgeon still debate about the long-term mortality issue
after release of exited five-year-old research and the data peak
issue, European association cardiac thoracic group. We did draw
the endorsement of a guideline so I think an additional stem we
require the individual patient level data analysis involving,
Excel, Nobel, Syntech and PRECOMBAT trial would be required to
provide the more definite compelling evidence for mortality
difference as well as the have the end point and including or so
some end point to repeat revascularization. We do allow
individual patient data analysis. That would be next. The short
step, next the long step, we definitely require extended
follow-up, Excel and Noble trial.


Dr Greg Hundley: Very good. Well listeners, this has been another
very informative feature discussion where we've compared PCI and
coronary artery bypass grafting in those with left main disease.
And now from this PRECOMBAT trial, 10 years of follow up showing
very similar outcomes related to death, myocardial infarction and
stroke in the two randomized arms. We want to thank Dr Duk-Woo
Park and Dr Manos Brilakis for presenting this information and as
we move forward, their insights as to next studies with newer
technologies and different examinations of stents. More long-term
follow-up from ongoing trials and then individualized patient
assessments.


Listeners, we hope you have a great week and hope everyone is
staying safe in this COVID crisis. Take care.


This program is copyright of the American Heart Association 2020.