Circulation May 12, 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, Director
of the Pauley Heart Center from VCU Health in Richmond, Virginia.


Well, our feature article this week, Carolyn, is really
interesting and evaluates management of patients that are
suspected to have atrial fibrillation and how we should screen
them, what kind of monitoring and the like, very interesting
discussion that will be coming up.


But before we get to that, how about we start into the papers and
would you like to go first?


Dr Carolyn Lam: I would love to. And the first one is a basic
paper on regenerative therapy, very important topic. Now remember
that mammalian adult hearts have limited regenerative capacity.
However, a transient regenerative capacity is maintained in the
neonatal heart.


So co-corresponding authors, Dr Wang and Dr Guo from Nanjing
Medical University hypothesize that by analyzing systemic
phosphorylation signaling in ischemic neonatal myocardium, they
may unlock key pathways involved in heart regeneration.


They therefore used quantitative phosphorylation proteomics to
analyze the kinase substrate network of regenerative myocardium
post MI in neonatal mice. And they found that activated Chk1
kinase was responsible for neonatal regeneration and could
enhance cardiac regeneration in adult hearts post MI via
activating the mTORC1 P70-S6K axis.


Dr Greg Hundley: Wow, Carolyn. Sounds like this could have a lot
of clinical application several years down the road. So what are
your thoughts on that?


Dr Carolyn Lam: I thought you may ask. Well, potentiation of Chk1
kinase, therefore, may be a promising regenerative therapy and
authors gave this example that Chk1 injection could for example,
in the form of a hydrogel, be injected into the myocardial
infarction region and surrounding areas and may even be a novel
therapeutic option to promote cardiac regeneration post MI.


Dr Greg Hundley: Very good, Carolyn. Well, my paper comes from
the PARTNER 3 trial and remember PARTNER 3 is a comparison of
transcatheter versus surgical aortic-valve replacement in low
risk patients.


The corresponding author is Dr Philippe Pibarot from Quebec. The
placement of aortic transcatheter valve three or PARTNER 3 trial
randomized a thousand patients with severe aortic stenosis and
low surgical risk at 71 centers to undergo either transfemoral
TAVR with the balloon expandable SAPIEN 3 valve versus undergoing
SAVR or surgical aortic valve replacement.


Transthoracic echocardiograms were obtained at baseline and at 30
days and one-year post procedure and they were analyzed by a
consortium of two echocardiography core labs.


The objective of this study is to compare echocardiographic
findings in low risk patients with severe aortic stenosis
following surgical or transcatheter aortic valve replacement.


Dr Carolyn Lam: Important topic, very hot. So what did they find?


Dr Greg Hundley: In patients with severe aortic stenosis and low
surgical risk, TAVR with the SAPIEN 3 valve was associated with a
similar percentage of moderate to severe AR compared with SAVR,
but a higher percentage of mild AR with no association between
any grade of AR and outcomes.


Trans-prosthetic gradients, valve areas and LV mass regression
were similar in TAVR versus SAVR. And SAVR was associated with a
significant deterioration of RV systolic function and greater
tricuspid regurgitation, which persisted at one year.


So Carolyn, very interesting results. Another study from PARTNER
3 comparing TAVR versus SAVR for patients with severe aortic
stenosis.


Dr Carolyn Lam: Nice. So going from PARTNER 3, I want to talk
about MESA and this time focusing on coronary artery calcium. Now
we know that the recent ACC/AHA primary prevention guidelines
recommend considering low dose aspirin therapy only among adults
who are at high atherosclerotic cardiovascular risk but not at
high risk of bleeding. However, it remains unclear how these
patients are best identified.


So the current study aimed to assess the value of coronary artery
calcium for guiding aspirin allocation in primary prevention
using the 2019 aspirin meta-analysis data on cardiovascular
disease relative risk reduction and bleeding risk.


So corresponding author Dr Cainzos-Achirica from Johns Hopkins
Ciccarone Center for the Prevention of Cardiovascular Disease and
colleagues studied 6,470 participants from MESA all of whom
underwent coronary artery calcium scoring at baseline to assess
benefit versus harm.


A 12% relative risk reduction in cardiovascular disease events
was used for five-year number needed to treat calculations, while
a 42% relative risk increase in major bleeding events was used
for the five-year number needed to harm estimations.


And now here are the results. Only 5% of MESA participants would
qualify for aspirin consideration for primary prevention
according to the ACC/AHA guidelines and using more than 20%
estimated atherosclerotic cardiovascular disease risk to define
higher risk.


Among the 3,540 aspirin naive participants less than 70 years old
and not at high risk of bleeding, the overall number needed to
treat in five years with aspirin to prevent one cardiovascular
disease event was 476, while the number needed to harm in five
years was 355.


The numbers needed to treat in five years was also greater than
or similar to the numbers needed to harm among estimated ASCVD
risk strata by pool cohort equations.


Conversely, with a coronary artery calcium score of more than a
hundred or more than 400, both these cutoffs identified subgroups
in which the number needed to treat in five years was lower than
the number needed to harm in five years.


Also, coronary calcium score of zero identified subgroups in
which the number needed to treat was much higher than the number
needed to harm.


Dr Greg Hundley: Lots of data. So we're mixing aspirin and MESA
coronary calcium scores. What do we take home from this?


Dr Carolyn Lam: So here's the take home message. Coronary artery
calcium may be superior to the pool cohort equations to inform
the allocation of aspirin in primary prevention.


Individuals with a coronary artery calcium score above hundred
and particularly above 400 may be good candidates for aspirin
therapy for primary prevention. Although the net expected benefit
will likely be modest.


In the presence of zero coronary artery calcium, the risk of
bleeding is greater than the potential benefit and aspirin
therapy for primary prevention should probably be avoided.


Overall, implementation of the current 2019 ACC/AHA guideline
recommendations together with the use of coronary artery calcium
scoring for further risk assessment may result in a more
personalized, safer allocation of aspirin for primary prevention.
Although ,of course, confirmation and external settings are
required.


Dr Greg Hundley: That was really interesting. Combining coronary
calcium scores, if you happen to have it, if someone's
considering primary prevention with aspirin, it looks like those
calcium scores could really be helpful there.


Well, I've got a couple other papers to talk about in this week's
issue. There's an ECG challenge from Abdulhamied Alfaddagh from
Johns Hopkins reviewing the quote unquote de Winter EKG pattern
in a truck driver presenting with chest pain.


Second, there's an in-depth article from Alexander Fletcher from
Edinburgh in the United Kingdom who discusses the metabolic
pathways involved in inherited aortopathies trying to move beyond
just diameter assessments to predict risk above future dilation
and rupture.


And then lastly, there's a research letter from Petra
Frings-Meuthen from the German Aerospace Center, the reports on
how weightlessness shifts intravascular volumes and concentration
of natriuretic peptides in astronauts.


Dr Carolyn Lam: Huh. And I would like one on my mind by Dr Kowey
and it talks about the relentless pursuit of new drugs to treat
cardiac arrhythmias.


Wow. What a nice issue. Let's move on now to our feature
discussion.


Dr Greg Hundley: Welcome everyone to our feature discussion. In
this particular paper will focus on atrial fibrillation and we're
delighted to have Dr Søren Diederichsen from Copenhagen
presenting this work and Dr Changsheng Ma, one of our associate
editors from Beijing, China to have nice discussion.


Søren, I was wondering if we could get started with you. Could
you tell us a little bit about what was the background related to
this study and perhaps even a little bit about the hypothesis
that you wanted to test?


Dr Søren Diederichsen:  The background for this study is
that, as we all know, atrial fibrillation is actually big and
it's a growing health problem throughout the world and we also
know that AF is often asymptomatic. So many cases of atrial
fibrillation go undetected until complications occur.


And, of course, one of the most feared complications from AFib is
a disabling stroke. And there's more and more evidence growing
that a large proportion of people with risk factors for stroke do
have some subclinical atrial fibrillation when they investigated
or when they are followed, for instance, with a pacemaker.


So there has been a recent meta-analysis that found that the at
risk of stroke in patients with subclinical AFib was fairly large
compared to the risk of stroke in patients without subclinical
AFib.


So, in this study, we want to look at the subclinical AFib in
patients from the general population using loop recorders to
follow these patients. And we want to sort of look at how could
we screen the patients to find those with subclinical AFib using
different screening scenarios which are less intensive than using
a loop recorder for everyone.


Dr Greg Hundley: Søren, could you tell us a little bit about your
study population and your study design?


Dr Søren Diederichsen:  First of all, this study is part of
an ongoing randomized control trial called the loop study. And in
the loop study we recruited study participants from the general
population.


The participants had to be at least 70 years old. And besides age
as a stroke risk factor, they also had to have at least one
additional stroke risk factor, hypertension, diabetes, heart
failure or previous stroke. And importantly, they could not have
AFib.


And the included participants were then randomized to control or
screening for AFib using implantable loop recorder with remote
monitoring and adjudication of new onset AF episodes.


In this particular study, we looked at the first participants in
the loop recorder group who had been monitored for the entirety
of the device's battery life, which is approximately three and a
half years. So for these persons, we know whether or not they
actually have AFib and we know exactly when they were in AFib and
when they were in sinus rhythm.


So we use this data from the loop recorders to reconstruct full
heart rhythm histories for each person, including exact time of
onset and termination of each episode after exclusion of any
clinically detected AF in the patients.


And it's a bit complicated study design because we have these
heart rhythm histories. Now you can imagine where we have a
string of data which is approximately three and a half years long
and we know exactly when is AFib present and when a sinus rhythm
present in this patient.


So we could use that data to simulate that the persons had been
invited to an AFib screening by the health care service and had
undergone a different type of screening at a random time. And
these screenings that we investigated were time-point screening
using standard ten second ECG during office hours and
intermittent screening using single list devices, for instance,
and short term continuous screening using external devices such
as Holter or event recorder.


So we simulated that the patients had undergone such screenings
and we could also assimilate that the patients were screened
several times on a monthly or annual basis such as, for instance,
taking an ECG every year.


And this simulation was then used to evaluate the sensitivity and
negative predictive value of various screening regiments using
the loop recorders' gold standard.


Dr Greg Hundley: What were your study results?


Dr Søren Diederichsen:  All of this data comprised, as I
told you, the first participant in our trial that had been
monitored for the full battery life of the device.


So that was 590 participants entering nearly 700,000 days of
continuous monitoring. So that was our data. And one third of
those participants actually had previously unknown AFib and the
number of AF episodes in our data was more than 20,000 AF
episodes.


The main results were that if we simulate the pseudo-random
daytime ECG in those patients, we would have identified only 1.5%
of those who had AFib while performing by daily 32nd ECGs during
14 days, we would have identified 8% of those with AFib.


And if we took a 72-hour Holter, we would have identified 15% or
a longer, for instance, a 30-day event recorder, we would have
identified about a third of all those with AFib.


So that was actually our main results. We were able to see how
many would we have identified of those with AFib if we'd done
anything from taking a daytime ECG to performing a rather long
event recorder.


Dr Greg Hundley: Were you able to put together maybe a
combination of other variables along with the more lengthy
recordings that could forecast future atrial fibrillation?


Dr Søren Diederichsen: One of the things we wanted to do with
this study was not only did we want to see what is actually the
diagnostic performance of doing an ECG or screening patients at
risk with different kinds of screening, we also want to look at
specific subgroups of the population who were more likely to
maybe benefit from the screening in terms of having their AFib
diagnosed.


So we looked at some population characteristics, age, sex and
NT-proBNP. And we saw that the sensitivity of the screening was
consistently higher among those who were older with a cutoff at
75 years, and also among males and among those with a high
NT-proBNP.


So we could see that if we had screened one of those risk factor
groups, age, male sex or high NT-proBNP, we would have been more
or less likely to identify if AF was actually present.


Dr Greg Hundley: Changsheng, I'd like to turn to you. Can you
help us put this results into perspective? How should we use this
information in managing patients with atrial fibrillation?


Dr Changsheng: The AI for screening is a very important clinical
problem and a hot topic issue. The heart rate monitoring is a
cornerstone for detecting suspected AF patients. And then
emerging new technology make monitoring more convenient than
before.


But however the best screening strategy for those at higher risk
of future AF stroke. And probably the strategy for the general
population screening remain undetermined.


On the contrary, they evaluated the performance of a large panel
of AF screening strategy among the 600 persons with a stroke risk
factor that was not known yet.


The study used as an implantable loop recorder as a gold standard
to assess the detection or difference in simulating a screening
model.


I've got to say, the method employed in this study is quite
exquisite and there's a key finding our clients tried to forward.


The time-point screening or the short-term monitoring could only
identify a very small fraction of AFIB as compared for long-term
loop recording screening. And diagnostic yield increased with
duration, number and the dispersion of screenings.


So this is done to provide important clinical implications that
every relatively intense screening such as even now I knew 30-day
monitoring would need more than four in ten with AF.


And about one in six which are underlying more than 24 hours
episode of AF. So the authors also gave the practical dispersion
concept that when screening for AF, three times 24 hour
monitoring are superior to one time 72 hour monitoring.


So I think this is a very important study to understand the
condition, to understand the screening of AF patient for the
general population.


Dr Greg Hundley: So really, helping us put these results in
perspective. Maybe I'll ask each of you Søren first and then
Changsheng. What do you think is the next research that needs to
be performed after taking your results into account?


Dr Søren Diederichsen:  In terms of what we should do next,
I agree with Changsheng that there's a lot of attention towards
AF screening at the moment, but we still really don't know if
widespread screening in the population is actually something that
could prevent heart endpoints.


So the next thing we need to know is, first of all, if we screen,
will we have fewer of those events or will we have more side
effects from the screening such as anticoagulant-mediated
bleedings? It's very important to keep in mind that we don't yet
know if screening is something that would prevent heart
endpoints.


Second of all, we want to know more about what is actually the
relationship between AF burden or amount of AF and risk of
stroke. There's some evidences coming up that it's growing.


Is it, for instance, from the CERT study that the amount of AF
and the pattern of AF that you have might tell us a little bit
about what is your risk of stroke? For instance, if you have long
AF episodes, your risk of stroke is higher than if you have all
the short AF episodes.


And so that would be two of the next things I would think we
should look at.


Dr Greg Hundley: Very good. Changsheng, do you have something to
add to that?


Dr Changsheng: Yes, I agree with Søren. Now, on the detection,
it's important but as a burden, even more important. So in
practice in future, wouldn't we need more advanced technology and
the patients or the participants frontally the monitoring device,
which has the same ability to loop record them.


But this is more easy to use because when we use frontal
monitoring for the patients, the longer duration of your
monitoring period. So worse complains to the patients, not as our
study because we have a simulation methodology, that 100% of
patient accomplishments.


So I think in future, the watch with a diagnostic function of AF
differentiation based on not ECG, but only based on the pulse.


So, the watch diagnostic function, not by ECG that are by pulse,
like a detection of pulse. And then depend on the artificial
intelligence, the AI function, to make a diagnosis of atrial
fibrillation, not by ECG. That would be the future.


Dr Søren Diederichsen:  And if you don't mind, I would like
to add to that because I think that Changsheng raises an
excellent point here with the smartwatch and how could they
contribute to our prevention of stroke and in society.


So the current smartwatches work by looking at the pulse by
photoplethysmography. And they cannot look at the pulse
continuously as we do with the loop recorder looking at the ECG
continuously.


This like with the photoplethysmography turns on when the patient
is at risk and builds up an algorithm to look at what is actually
the likelihood that the patient is an AF at this moment or today.


So at this point it'll only detect fairly long AF episodes, but
in this study, we also looked at the longer AF episodes and the
AAF burden. How does that impact the likelihood of detecting AF
and of course it's more easy to detect it in patients with long
AF episodes.


And if we find out in the future that a larger AF burden or
longer AF episodes are actually required to increase the risk of
stroke, then I believe that technology such as smartwatches could
be a very feasible way to screen or to detect that kind of AF in
patients at risk.


Dr Greg Hundley: Well listeners we've had a wonderful discussion
here with Dr Søren Diederichsen from Copenhagen and our associate
editor, Changsheng Ma from Beijing, China.


And really reviewing some important results related to screening
for atrial fibrillation and the three 24-hour monitoring sessions
combined with risk factors really help us identify who may be
experiencing atrial fibrillation in our patients.


And then also, very interesting projections for the future, both
using technology to try to identify atrial fibrillation perhaps
through watches.


And then also how we could incorporate the duration, the time, et
cetera of atrial fibrillation occurrences and how they may relate
to adverse events.


Thank you so much Søren. Thank you Changsheng. And to all our
listeners, we wish you a very safe week and look forward to
meeting with you next week. Take care.


This program is copyright the American Heart Association 2020.