Circulation June 20/27, 2017 Issue

Dr. Carolyn
Lam:              
Welcome to Circulation on the Run your weekly podcast summary and
backstage pass to the journal and it's editors. I'm Dr. Carolyn
Lam, associate editor from the National Heart Center and Duke
National University of Singapore.


                                               
Is it time to end our debates on short versus long duration of
dual anti-platelet therapy? Well I will be discussing this with
two very special guests in just a moment. But first here is your
summary of this week's journal.


                                               
The first paper tells us that HDL particle number may serve as a
biomarker of residual risk when assessed on statin therapy. First
author Dr. Khera, corresponding author Dr. Mora from Brigham and
Women's Hospital and colleagues of the JUPITER trial assessed HDL
cholesterol levels, apolipoprotein A-1, cholesterol efflux
capacity and HDL particle number at baseline and 12 month in a
nested case control study of the JUPITER trial. That was a
randomized primary prevention trial that compared rosuvastatin to
placebo in individuals with normal LDL but increased CRP levels.


                                               
In the current study the authors found that cholesterol efflux
capacity was moderately correlated with HDL cholesterol, apoA-I,
and HDL particle number. Baseline HDL particle number was
inversely associated with incident cardiovascular disease, while
there was no significant association for baseline cholesterol
efflux capacity, HDL or apoA-I levels. On-statin cholesterol
efflux capacity was inversely associated with incident
cardiovascular disease but HDL particle number again emerged as
the strongest predictor.


                                               
Thus for both baseline and on-statin analyses, HDL particle
number was the strongest of four HDL-related biomarkers as an
inverse predictor of incident events and biomarker of residual
risk.  Whether therapies designed to enhance cholesterol
efflux capacity or an increased HDL particle number can also
reduce cardiovascular risk however remains uncertain.


                                               
The next study sheds light on mechanisms underlying the
de-differentiation and lineage conversion of adult human
fibroblast into functional endothelial cells. First author Dr.
Zhang, corresponding authors Dr. Rehman and Malik from University
of Illinois College of Medicine first generated CD34+ progenitors
by de-differentiating adult human skin fibroblasts and showed
that these intermediate progenitors could give rise to
endothelial cells as well as erythrocytes. They then showed that
lineage conversion of fibroblasts via partial de-differentiation
recapitulated in part the embryonic development of the
vasculature as evidenced by up regulation of anti-aging enzyme
telomerase and the bi-lineage potential of the generated
progenitors.


                                               
Importantly they showed that transcription factor SOX17
functioned as a switch which regulated the cell fate of CD34+
progenitors towards an endothelial versus erythroid lineage.
Finally implanted fibroblast derived CD34+ progenitors stably
engrafted to form functional human blood cells in mice that
improved cardiac function after myocardial infarction. Thus the
molecular switch SOX17 provides a means to optimize the
generation of endothelial cells for vascular tissue regeneration
or disease modeling.


                                               
What do drones have to do with out of hospital cardiac arrest?
Well in this next study by first author Dr. Boutilier
corresponding author Dr. Chan and colleagues from University of
Toronto, the authors hypothesized that a drone network designed
with the aid of a mathematical model combining both optimization
and queuing could reduce the time to AED arrival.


                                               
Using data from over 50,000 historical out of hospital cardiac
arrests covering over 26,000 square kilometers in Ontario,
Canada, they found that a drone network designed to reduce the
median AED arrival time by three minutes relative to the
historical 911 response could also reduce the 90th percentile of
the AED arrival time by between 6 minutes and 43 seconds in most
urban regions and 10 minutes and 34 seconds in most rural
regions.


                                               
Thus this study tells us that drone delivered AEDs have the
potential to be a transformative innovation in the provision of
emergency care to cardiac arrest patients especially those who
arrest in a private or rural setting.


                                               
The next study provides thresholds for ambulatory blood pressure
among African Americans. Dr. Ravenall and colleagues from New
York University School of Medicine analyzed data from the Jackson
Heart Study, a population-based cohort comprised exclusively of
African-American adults and of whom more than 1000 participants
completed ambulatory blood pressure monitoring at baseline.


                                               
Based on the outcome derived approach for systolic blood pressure
and a regression derived approach for diastolic blood pressure,
the following definitions corresponded to clinic blood pressure
of 140/90 and were proposed as ambulatory blood pressure
definitions for African Americans. Daytime blood pressure above
140/85, 24 hour blood pressure above 135/80 and nighttime blood
pressure above 130/75 mmHg. Note that these ambulatory blood
pressure thresholds identified for African Americans were higher
than those from published recommendations mainly derived in
European, Asian and South American populations. The use of these
ambulatory blood pressure thresholds for African Americans will
lead to a lower prevalence of daytime, 24 hour and nighttime
hypertension compared with the current published recommendations.


                                               
The next paper provides pre-clinical evidence of a novel target
in plaque information in atherosclerosis. Dr. Stachon and
colleagues from Heart Center Friburg University in Germany
hypothesized a functional role of the signal axis ATP binding to
purinogenic receptor P2X7 in inflammasone activation and chronic
inflammation driving atherosclerosis.


                                               
In an elegant series of experiments they showed that P2X7
receptor activation was crucial for inflammasone assembly and
interleukin-1-beta secretion. The lack of P2X7 in mice abolished
inflammasone activation in atherosclerotic lesions. P2X7 was
expressed in murine and human atherosclerotic lesions. LDL
receptor deficient mice lacking P2X7 receptor had reduced plaque
inflammation and were less prone to develop atherosclerosis.


                                               
Thus this study shows that P2X7 inhibition could be a treatment
strategy against plaque inflammation in atherosclerosis.


                                               
The next paper describes the first prospective clinical study of
adenosine use in pediatric and young adult patients after heart
transplantation. Now prior to this study adenosine was relatively
contraindicated post-transplant due to a presumed risk of
prolonged atrioventricular block in denervated hearts.


                                               
In the current study first author Dr. Flyer corresponding author
Dr. Silver and colleagues from Columbia University performed a
single center prospective clinical study testing whether
adenosine caused prolonged asystole after transplant and if it
was effective in blocking AV nodal conduction in healthy heart
transplant recipients aged 6 months to 25 years presenting for
routine cardiac catheterization. Following catheterization, a
transvenous pacing catheter was placed and adenosine was given
following a dose escalation protocol until AV block was achieved.


                                               
Eighty patients completed adenosine testing. And no patient
required rescue ventricular pacing. AV block was observed in 77
patients with the median longest AV block of 1.9 seconds and the
mean duration of adenosine effect of 4.3 seconds.


                                               
Thus, this study suggests that adenosine may be safe and
effective in patients post transplantation and establishes both a
safe and effective starting dose of 25mcg/kg or 1.5mg for
patients weighing 60kg and more. It also establishes a stepwise
therapy escalation plan to avoid prolonged bradycardia. Although
patients after heart transplantation may require less adenosine
to achieve AV block it appears to be safe and effective as
therapy for evaluation and or treatment of tachycardia in this
population.


                                               
Well those were your summaries, now for our feature discussion.


                                               
Today for our feature discussion we are talking about a very
familiar situation, dual anti-platelet therapy following coronary
intervention and the decision of long versus short duration of
therapy. A debate we've heard many times but according to the
perspective piece in today's journal, maybe a debate we should
end. And I am so pleased to have the author, Dr. Glenn Levine
from Baylor College of Medicine as well Dr. Laura Mauri associate
editor from Brigham and Women's Hospital.


                                               
Welcome both.


Dr. Laura
Mauri:              
Thank you Carolyn.


Dr. Glenn
Levine:            
Thank you.


Dr. Carolyn
Lam:              
Glenn would you like to start by presenting your case. It's time
to end a dualistic short versus long duration of DAPT debate. I
really like that title, tell us more.


Dr. Glenn
Levine:            
Thank you Carolyn.


                                               
The point we make in our editorial is that over the last five or
six years there have been studies comparing what I term standard,
which is usually about 12 months DAPT versus shorter duration
DAPT and there are other studies comparing standard DAPT versus
longer duration DAPT. Those generated important information in
different people interpret them in different ways. What though
has happened over the last several years is certainly for both
educational and entertainment value at meetings as well in
editorials, the idea of how long people should be treated with
DAPT has been oversimplified to whether all patients should be
treated with short duration or long duration. And Laura herself
knows that as she has been in many of these debates.


                                               
While I think that initially that was educational and
entertaining, I think these days people understand those points
and a greater issue is in that we should treat some people with
short duration, some with what I call standard and some with long
duration. And rather than debating whether everyone should
treated with short or everyone should be treated with long, I
think what we need to focus on now is which patients should be
treated with short duration, which are probably best treated with
a standard duration and which are best treated with prolonged or
extended duration DAPT.


                                               
And that in a nutshell is the main point that we make in this
perspective editorial.


Dr. Carolyn
Lam:              
Laura, so do you agree?


Dr. Laura
Mauri:              
I couldn't agree more. I think clinicians really are looking for
guidance and what happens at these debates is you see these
polarizing opinions that debaters are asked to defend when in
actuality there's such a wide spectrum of what individual
patients need. And the real question I think going forward is how
to end these debates and how to provide really more tailored
information so clinicians and patients can make better decisions
together. And I think that's really where the piece that Glenn
has written really helps direct us.


Dr. Carolyn
Lam:              
Yeah, Glenn, I mean are we talking about the usual risk versus
benefits and precision metsan or individualized risk assessment
here?


Dr. Glenn
Levine:            
Yeah, what we're talking about is looking at the ischemic risks
which are primarily leg stent thrombosis or spontaneous MI versus
the bleeding risks which is obviously bleeding and balancing
them. And there clearly are decision tools available to
clinicians. Laura has pioneered the DAPT score which is an
incredibly user friendly and easy tool to use to assess which
patients should be continued with prolonged DAPT or not. And
there are also some other tools out there including the Paris
registry score perhaps a little more complex and then there's
also now the precise DAPT score which one can at least assess
bleeding risk and indirectly assess the ischemic and bleeding
risk.


                                               
But really I think that is the focus now on balancing bleeding
and ischemic risks and having pools to allow clinicians to easily
do that.


Dr. Carolyn
Lam:              
That's true. Now do you think guidelines have to catch up or have
they caught up?


Dr. Glenn
Levine:            
Our DAPT duration guideline was coming out just as Laura's DAPT
score was about to be published, several months after it had been
presented. And we did mention the DAPT score in our paper, it was
too early to formally incorporate it into the guidelines.
Nevertheless, the way our guidelines are written, they clearly
give practitioners the option for individualizing therapy based
on ischemic and bleeding risk and Laura's DAPT score fits
perfectly into what we aim to do, namely to encourage
practitioners to assess patients on an individual level and
assess what duration of DAPT is best.


Dr. Carolyn
Lam:              
I do have a question for Laura here though. I see Asian patients,
I'm talking to you here from Singapore. And sometimes you wonder
the trial situations and what you derive there. How does it
differ from real world and how is it impacting your practice for
example Laura?


Dr. Laura
Mauri:              
That's a great question. I think you have a number of points
there. One is the generalized ability or results from one trial
across the world where you might have many different patient
populations. And while the DAPT score was an international trial
it would be interesting to see more data coming out from other
different countries. And as you know there are trials in Asia
that have looked at randomized DAPT duration as well.


                                               
I think now that we have better access to information especially
in cardiology globally, we can get that information and better
tailor therapy. When we look at any one randomized trial the
results might seem kind of black and white and to certain extent
so do guideline recommendations but we are getting better at
using the results from randomized trials to really identify risk
factors. I think that with time we'll be able to either validate
the DAPT score in other patient populations or develop tailored
scores from unique data sets. I think the challenge really is
making sure that we still get good randomized evidence for our
treatment decisions but then when we have treatments that have
both benefit and risk that we identify which sub-populations of
patients really do achieve most of the benefit. And then the
other populations that might be harmed. And that's really what we
try to do with this score.


                                               
And I think what you'll see, you asked about precision medicine
which usually we think about using genetics but I think there's
so much just really basic information that we have about patient
lesion characteristics and other specific factors that we record
routinely in their medical records that we can use and you'll see
this, I think more and more frequently across different areas of
investigation and in cardiovascular medicine.


                                               
One really interesting example recently was this French trial.
Data was used to be able to predict, very similar to what we did,
but to predict which patients would benefit from lower blood
pressure without the risk of more aggressive treatment.


Dr. Carolyn
Lam:              
Yeah, I love the way you put that. Those are really words of
wisdom, I do think that that is the way cardiovascular medicine
is gonna move. Glenn, how do you put all this into practice for
yourself?


Dr. Glenn
Levine:            
I think whether or not I formally calculate a DAPT score or Paris
registry score, I think clearly we integrate the factors in those
scores into our everyday practice. And clearly there are patients
who are at high bleeding and low ischemic risk and vice versa. I
would also encourage listeners to in addition to all the scores,
one has to think about the consequences of a recurrent MI or
stent thrombosis. Obviously someone who has stent thrombosis of a
proximal LED lesion, if they already have a depressed EF or
occluded RCA, those consequences are likely much more dire then
someone who occludes say at a distal OM3 stent who has the normal
ejection fraction. It also encourages them to think about the
consequences of stent thrombosis as well as the consequences of a
recurring MI.


Dr. Laura
Mauri:              
Just to make it clear, we know that clinicians have always tried
to balance these different risks of ischemia and bleeding when
faced with this decisions. I think the challenge really has been
the limited amount of information that we've had to be able to do
that. And so we've really just used kind of our gut until
recently when we've had several large randomized data sets to be
able to look to. And what that's done is it's given us the
ability to construct these new tools to be able to make practice
more data driven. Now still individualized but based on data
that's tailored to our patients.


                                               
And so I think we can use that to be able to improve outcomes.
That being said, we don't want to rely on a statistic or a score
alone and things like the DAPT score are based on patients like
the ones that were enrolled into the randomized trial. Those were
patients who could take longer anti-platelet therapy. It helps to
identify who can take it for longer. But there are patients who
get anti-coagulation or have other serious bleeding risks who
really are going to benefit from new technologies to be able to
shorten anti-platelet therapy.


Dr. Carolyn
Lam:              
Well thank you Glenn once again for a wonderful perspective piece
that has really got us thinking about situations even beyond dual
anti-platelet therapy. Thank you Laura for your insights and
thank you listeners for joining us today. Join us again next
week.