Circulation August 11, 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 Dr Greg Hundley, associate editor,
director of the Pauley Heart Center, VCU Health in Richmond,
Virginia.


Dr Carolyn Lam: Greg, guess what we're discussing for the feature
discussion? We're talking about sugar sweetened beverage tax.
Isn't that interesting? We talk about sugar sweetened beverages
and their health impacts, but don't actually look at how tax
policies may impact cardiovascular outcomes. So this paper is
super interesting, can't wait to get to it, but I really want to
get my cup of coffee and discuss a couple of other really cool
stuff in today's issue. I'm going to start. Do you think about
factor V Leiden much?


Dr Greg Hundley: Carolyn, we are early in August and we have all
new house officers rotating, and actually we do discuss factor V
Leiden, and we think about Protein C and Protein S deficiencies,
et cetera. But how about if you tell us about your paper and
educate us a little bit more on the topic?


Dr Carolyn Lam: Okay. So first of all, it's Leiden or Leiden, I'm
not sure. So I'm going to go with your pronunciation. Factor V
Leiden is a genetic variant leading to alteration of the
inactivation site of factor V, which in turn leads to activate a
Protein C resistance and a prothrombotic state, just like you
said, Greg. Affecting almost 5% of the Caucasian population,
carriers of a factor V Leiden mutation have a fourfold higher
risk of venous thromboembolism. However, the risk of arterial
atherothrombotic events, such as myocardial infarction or stroke,
conferred by the presence of this variant is less certain. So Dr
Patel from University College London, and Dr Asselbergs from
University Medical Center Utrecht and colleagues assess the
association of the factor V Leiden polymorphism with subsequent
atherothrombotic events, including mortality in individuals with
established coronary heart disease using an individual level data
meta-analysis of 25 prospective studies from the genetics of
subsequent or GENIUS coronary heart disease consortium.


Dr Greg Hundley: Well Carolyn, what did they find?


Dr Carolyn Lam: In nearly 70,000 patients with established
coronary heart disease, factor V Leiden was not associated with
an increased risk of further atherothrombotic events or death
compared to non-carriers. A post hoc analysis, however, suggested
that factor V Leiden carriers with established coronary heart
disease may gain greater protection from subsequent coronary
heart disease, death, or myocardial infarction from dual
antiplatelet therapy compared to non-carriers. The routine
assessment of factor V Leiden genotype to improve risk
stratification in secondary prevention settings is therefore
unlikely to be of value and is not recommended. However, further
work is required to understand if there may instead be a
pharmacogenomic role for factor V Leiden status to help
personalize treatment with intensive antiplatelet therapy.


Dr Greg Hundley: Very nice, Carolyn. Well, my next paper is from
Dr Michelle O'Donoghue from Brigham and Women's Hospital, and
creates an interesting question for you, Carolyn. Would you be
comfortable discontinuing aspirin three months after PCI in lieu
of continuing a P2Y12 inhibitor?


Dr Carolyn Lam: Ah, big, big question. Not until guidelines
change, but tell me, tell me, tell me, Greg, what this paper
said.


Dr Greg Hundley: Well, before we get some of these more
randomized trial, this study included a meta-analysis of 32,145
patients, 14,095, or 43%, with stable coronary artery disease and
18,000, nearly 56%, with ACS from randomized trials during the
time period of 2001 to 2020. And they had to study discontinuing
aspirin one to three months after PCI with continued P2Y12
inhibitor monotherapy compared to traditional dual antiplatelet
therapy. Five trials were included, and the follow-up duration
range from 12 to 15 months after PCI. The primary bleeding and
MACE outcomes were the pre-specified definitions in each trial.


Dr Carolyn Lam: An important study. So what did they find, Greg?


Dr Greg Hundley: Well in the experimental arm, background use of
a P2Y12 inhibitor with Clopidogrel in 16.5% of cases, and
prasugrel or ticagrelor in 84% of patients. In total, 820
patients experienced a primary bleeding outcome and 937
experienced MACE. So the results, discontinuation of aspirin
therapy one to three months post PCI significantly reduced the
risk of major bleeding by 40% compared to dual antiplatelet
therapy with no observed increase in the risk of MACE, myocardial
infarction, or death. The findings were consistent among patients
who underwent PCI for an ACS in whom discontinuation of aspirin
after one to three months reduced bleeding by 50%, to 1.78%
versus 3.58%, and did not appear to increase the risk of MACE
where both were 2.5% and 2.98%.


Dr Carolyn Lam: Nice, Greg. Could you summarize the take home
message for us?


Dr Greg Hundley: Sure, Carolyn. So in summary, discontinuation of
aspirin with continued P2Y12 inhibitor monotherapy reduced the
risk of bleeding when stopped one to three months after PCI. An
increased risk of MACE was not observed following discontinuation
of aspirin, including patients that had previously sustained ACS.


Dr Carolyn Lam: Thanks Greg. Well, my next paper is a preclinical
one showing that circular RNAs delivered via extracellular
vesicles may be a new treatment for ischemic stroke.


Dr Greg Hundley: Oh my goodness. Carolyn, can you orient us to
circular RNAs and these extracellular vesicles?


Dr Carolyn Lam: Sure, Greg. I decided not to quiz you on them.
Circular RNAs are a type of endogenous non-coding RNA molecule
characterized by back splicing and covalently closed continuous
loops, hence circular. Previous studies have demonstrated that
multiple circular RNAs have functional roles relating to ischemic
brain injury. Although administering circulating RNAs using
lentiviruses is efficient for experimental examination, this
route is limited for clinical translation due, of course, to
disadvantages in onset time and safety issues. So this is where
the extracellular vesicles come in as a potential cargo
delivering system, if you may, for brain remodeling after stroke.
These extracellular vesicles are lipid membrane vesicles of 30 to
150 nanometers in diameter that are released by cells and can
cross the blood brain barrier and have been shown capable of
carrying proteins, lipids, and nucleotides as their cargo.


So today's co-corresponding authors, Dr Yao from Medical School
of Southeast University in Nanjing, and Dr Wang from Chinese
Academy of Sciences Kunming, Yunnan in China envisioned the
potential of delivering candidate circular RNAs to the brain in
vivo by constructing engineered extracellular vesicles bearing
circular RNAs. They initially explored this circular RNA delivery
strategy idea in the context of their ongoing work regarding the
functional roles of circulating RNAs in ischemic brain injury.
Their microarray based profiling of acute ischemic stroke
patients reveal that a circular RNA generated from the
SCM-polycomb group protein homolog 1, or SCMH1 gene, is decreased
in plasma of acute ischemic stroke patients and confirmed that a
similar decrease occurs in stroke model mice. So they
successfully engineered extracellular vesicles with circular
SCMH1 over-expression and were thus able to experimentally
characterize the ischemia related functional benefits of this
circular RNA administration in stroke models in both mice and
macaque monkeys. Cool, huh?


Dr Greg Hundley: Yeah. Very nice, Carolyn. That was a great
explanation. My study comes from Dr Juyong Kim from Stanford
University School of Medicine, and Carolyn, this study combined
RNA sequencing, chip sequencing, ATEC sequencing, and in vitro
assays in human coronary artery smooth muscle cells with single
cell RNA sequencing, histology, and RNA scope in a smooth muscle
cell specific lineage tracing aryl hydrocarbon receptor knockout
mouse model of atherosclerosis to better understand the role of
the aryl hydrocarbon receptor in vascular disease. This aryl
hydrocarbon receptor, heretofore AHR, is an environment sensing
transcription factor that contributes to vascular development.


Dr Carolyn Lam: Wow, what a comprehensive study. So what do they
find?


Dr Greg Hundley: The authors identified a novel population of
cells derived from smooth muscle cells, termed condramyocytes,
which have gene expression features of cartilage and bone
formation within an atherosclerotic lesion. In addition, the
environment sensing transcription factor aryl hydrocarbon
receptor plays an important role in smooth muscle cell
differentiation, ossification, and maintains the smooth muscle
cell derived fibrous cap structure.


Dr Carolyn Lam: Interesting. Okay, you know what I'm going to
ask. What are the clinical implications?


Dr Greg Hundley: Yeah, I knew you'd ask me that, Carolyn. So
human genetics suggests a protective role of the aryl hydrocarbon
receptor in the smooth muscle cell during atherosclerosis, and
therapies targeted to increase the aryl hydrocarbon receptor
activity in smooth muscle cells may confer protection against
adverse calcific remodeling of the atherosclerotic plaque. This
study also highlights a methodological advance, and further
characterization of the pathways that direct the modulation of
smooth muscle cells during atherosclerosis at the single cell
level may be able to identify potential therapeutic targets to
mitigate the risk of atherosclerosis.


Dr Carolyn Lam: Oh, I like that summary, Greg. Thanks. Now, let's
move on to other things in today's issue. There's a perspective
by Dr Al-Lamee on the ISCHEMIA trial asking was it worth the
wait? There's also a perspective by Dr Levine on the ISCHEMIA-CKD
trial, providing contemporary randomized clinical data at last in
this important population. There's a white paper by Dr Emmaullee
on Fontan-Associated Liver Disease, screening, management, and
transplant consideration. And finally, there are letters to the
editor from Dr Helgestad, Chieffo, and Waksman, with replies from
Dr Amin on the article The Evolving Landscape of Impella Use in
the United States Among Patients Undergoing PCI With Mechanical
Circulatory Support.


Dr Greg Hundley: Very good, Carolyn. Well, I have a few other
items in the mail bag. Xiang Cheng has a research letter entitled
Cardiac Troponin I is an Independent Predictor for Mortality in
Hospitalized Patients with Coronavirus Disease 2019. Also,
Corinne Frere has a research letter regarding the Systemic
Inflammatory Response Syndrome is a Major Contributor to
COVID-19-Associated Coagulopathy, and they provide insights from
a perspective single center cohort study. And finally, Dr Jeffrey
Wagner has an ECG challenge regarding the infamous is it VT or
not VT? Well, Carolyn, how about we get on to that feature
discussion.


Dr Carolyn Lam: Let's go, Greg. Beverage Texas are a promising
policy approach to reduce consumption of sugar sweetened
beverages. And as we know, these are linked to adverse health
outcomes, such as Type 2 diabetes and obesity. Now these taxes
have been adopted by seven localities in the United States, and
in more than 40 countries around the world using different tax
designs, but until now a critical answered question where we lack
empirical data is the health impact of these beverage taxes. That
is until today's feature paper, and I'm so pleased to have with
us, Dr Yujin Lee from Friedman School of Nutrition Science and
Policy, Tufts University, as well as our associate editor, Dr
Naveed Sattar from University of Glasgow. Welcome both, and
Yujin, could I start with you please? What an interesting and
important idea to look at this. Could you start by perhaps first
explaining to us what are the different types of tax designs?


Dr Yujin Lee: There are three types of tax design. First, the
volume tax is taxing sugar sweetened beverages based on the
volume. For example, a penny per owns for volume tax. So the tax
rate is same whether a beverage contains 5 or 20 grams of added
sugar for 8 ounces. The second design is the absolute sugar
content tax, which is taxing beverages based on the sugar content
regardless of the volume. So for example, one cent per one
teaspoon of sugar, or one cent per one gram of sugar. Lastly,
tier tax is hybrid of volume and absolute sugar content tax. For
example, creating different tiers products based on the sugar
content and taxing based on the volume at different rates. So for
example, the American Heart Association suggested three tiers.
First, no tax on beverages with less than five grams of added
sugar per eight ounces. And second, 1 cent per ounce on beverages
with 5 to 20 grams of added sugar per 8 ounces. And lastly, 2
cents per ounce on beverages with more than 20 grams of added
sugar per 8 ounces.


Dr Carolyn Lam: Great. So thank you for explaining that. I mean,
to be honest, I didn't even realize there were so many different
tax designs. Now, could I understand a bit better? So in the US,
are they mostly volume-based? And then perhaps you could tell us
how did you go about your study of comparing these things, and
looking on their impact on outcomes.


Dr Yujin Lee: Sure. So as you mentioned, all seven US locality
have been implementing the volume tax, and in this study, this is
the modeling study, so we're using the nationally representative
data and using a microsimulation model, and we wanted to compare
and estimate the health and economic impact of the volume,
absolute sugar content. And the tier tax designs in the United
States.


Dr Carolyn Lam: Great. And tell us what you found.


Dr Yujin Lee: What we found is we found that implementing a
volume-based sugar sweetened beverage tax could prevent 850,000
cardiovascular events and 270,000 diabetes over a lifetime of
current US adults aged 35 years or older. And this tax design
could save tens of billions of dollars in healthcare costs. In
addition, taxing sugar sweetened beverage based on their sugar
content, for example, the tier or absolute sugar content based
tax design, could generate about double the health and economic
benefits compared to the volume tax.


Dr Carolyn Lam: Wow, that is so intriguing. Naveed, I have to
bring you in here. So in the UK they use a tier tax. Do you? And
what are your thoughts?


Dr Naveed Sattar: Oh, well clearly, Carolyn, I mean, I think
taxation of sugar sweetened beverages is something that all of us
can agree on is beneficial. I think it's really important that
many other countries and states consider this. I'm surprised that
only seven states in the US are currently doing this. And in some
respects, this papers is very timely. It's based on modeling. I
mean maybe you can come back to Yujin about how good the modeling
is, but if you think about the issue we have now in terms of
health inequalities and COVID related deaths, going forward we
need mechanisms to help reduce health inequalities. And this
particular paper will flag up that places need to think about
sugar sweetened beverage taxes and how best to do them.


And I completely agree, they should be based on sugar content. I
don't see why they should be more convoluted than that. And
although Yujin explained it, it still seems a bit complex to me,
the different mechanisms, but I think your paper is very timely
and very important. And for me, the key question for Yujin is
people looking at this may say well, how robust is that model?
How do we know how accurate you've been in terms of the money
saved, because that's going to be really important going forward,
and in particular, the number of lives or cardiovascular and
diabetes cases prevented?


Dr Yujin Lee: Sure. So let me explain how we estimated how many
cases of cardiovascular disease and Type 2 diabetes were
prevented. So we use a microsimulation model, which is a computer
simulation model, which is developed by the research team, led by
Dr Thomas Casiano and Harvard School of Public Health. So this
model predicts the probability of an individual experiencing
cardiovascular disease or diabetes based on each person's risk
factor, such as sex, age, total cholesterol, or smoking or
diabetes, and also their SSB-consumption also be part of this
input. So it estimate the probability of one person, individual,
developing the future cardiovascular disease, or Type 2 diabetes,
and it estimate how this prevention can save healthcare costs
associated with these diseases. So in this study, this model
simulates the status quo, so the way things now stand, and also
it assimilate the three different tax design. After that, we
compute the health outcome and costs associated with this policy
options and, by comparing this model, outputs for these three tax
design with the status quo.


Dr Naveed Sattar: Has any country got long enough perspective
data that have implemented such taxes to validate the model, or
is that still to come? I mean it would be nice to get it
validated in real life, but I think most people would accept that
reducing sugar in beverages is a really good thing, and
presumably the part of the mechanisms by reducing weight, and
reducing all of the implications of excess calorie intake,
particularly refined sugar, on a variety of different diseases.
Is that fair?


Dr Yujin Lee: Yeah, and I wanted to make a point that, since this
is a modeling study, so our study cannot prove the health and
economic impacts of this tax design in the United States, so
rather our estimates provide evidence that can be considered and
incorporate into the design, and implementation, and evaluation
of future SSB taxes.


Dr Carolyn Lam: That's a really good point. And maybe just to
round up, Yujin, could I just ask you to were any particular
individuals in the population simulated to experience larger
gains? We know that it's exactly like Naveed said, it's the
minorities, it's perhaps lower income region individuals who
might need this more. I mean did your simulation show anything to
that effect?


Dr Yujin Lee: We also investigate this tax design and how this
influence in sub population. Particularly we found that the SSB
taxes have a larger benefit among younger adults, minorities, and
adults with the lower income. Given that these population, their
SSB consumption is higher than the other group, so this SSB tax
implementation gives them a greater health and economic benefit
to these subpopulations.


Dr Carolyn Lam: Thank you so much, Yujin, for this really,
really, I think, novel and very important data. Naveed, could I
give you the last say as the associate editor who is managing
this, and you even invited an editorial, which I liked very much,
the title, Simple is Better for Local Beverage Tax Policy
Diffusion. It's kind of in line with what you've been saying, but
maybe some take home messages?


Dr Naveed Sattar: Obviously in Circulation, we get lots of
beautiful papers that very molecular depth and various other
factors, but actually this paper brings us back to the reality
that for many of the diseases that we treat, diet and drink
intake is really relevant to our diseases and the likelihood of
diseases, and there are simple mechanisms whereby we can help
people in the community to actually lead better lifestyles that
also are actually economically beneficial. And I think that in
this paper, if it was to be implemented and looked at seriously
by many states in the US, by many other countries to go along
this route would have huge potential benefits on health, And it's
really important at this time, given what's happened with the
pandemic, and as we move forward over the next 5 to 10 years. So
I think it's really timely and I congratulate the authors on it.


Dr Carolyn Lam: Well, listeners, you heard it right here, novel,
impactful data. That's what Circulation is about. Thank you for
listening to Circulation on the Run. Don't forget to tune in
again. Next week.


Dr Greg Hundley: This program is copyright the American Heart
Association, 2020.