Circulation August 25, 2020 Issue

This week’s episode of Circulation on the Run has 2 Feature
Discussions. Associate Editor Ntobeko Ntusi discusses the article
"Prevalence of Infectove Encocarditis in Streptococcal
Bloodstream Infections is Dependent on Streptococcal Species."
Then, author Anumpam B. Jena and Associate Editor Sandeep Das
discuss trends in new diagnoses of atrial fibrillation after the
release of an ECG-capable smartwatch.


TRANSCRIPT:


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 from
the Pauley Heart Center at VCU Health in Richmond, Virginia.
Well, Carolyn, our feature this week involves infective
endocarditis and looking at that in streptococcal bloodstream
infections. Are they dependent on the different species of
streptococci? But before we get to that, how about we grab a cup
of coffee and start off and discuss other papers in the issue.
You want to go first?


Dr Carolyn Lam: Sure, Greg. I got my coffee, but I want to start
with a quick question. So do you think it's safe and efficacious
to prescribe SGLT2 inhibitors to patients with Type 2 Diabetes
and concomitant peripheral artery disease?


Dr Greg Hundley: Ah, Carolyn, very good question. I don't know if
it's right or wrong. A little bit of controversy here.


Dr Carolyn Lam: Let's explain that controversy. So patients with
peripheral artery disease are at heightened risk of
cardiovascular complications. However, there's also an increased
risk of amputation that was observed with canagliflozin in one
prior trial. Now, the SGLT2 inhibitor dapagliflozin was shown to
reduce the risk for hospitalization for heart failure and kidney
events in patients with Type 2 Diabetes in the DECLARE–TIMI 58
trial. So authors Dr Bonaca from University of Colorado School of
Medicine and colleagues examined the cardiovascular and kidney
effects and the risk of limb related events in patients with and
without peripheral artery disease in the huge DECLARE–TIMI 58
trial, including more than a thousand patients with peripheral
artery disease.


Dr Greg Hundley: So this could be really helpful to answer this
question. What did they find, Carolyn?


Dr Carolyn Lam: Well, patients with versus without peripheral
artery disease were indeed at higher risk of major adverse
cardiovascular events, cardiovascular death, or heart failure,
hospitalization and kidney events. They also had consistent
benefits for the outcomes of cardiovascular death or heart
failure hospitalization as well as progression of kidney disease
with dapagliflozin. Now ,patients with peripheral artery disease
also had a higher risk of limb events, but there was no
consistent pattern of incremental risk observed with
dapagliflozin. So the take home, diabetes patients with
peripheral artery disease are at risk of heart failure and kidney
events and dapagliflozin is beneficial with no patterns of
increase limb risk.


Dr Greg Hundley: Very nice, Carolyn. Boy, that is very helpful
and a nice take home message for all of us administering these
agents. Well, Carolyn, my first study comes from Professor Magnus
Bäck from the Koralinska Institute. And the aim of this study was
to identify the role of omega−3 polyunsaturated fatty acids,
derived specialized pro resolving mediators, or SPMs, in relation
to the development of aortic valve stenosis. The synthesis of
specialized pro resolving mediators are potent beneficial
anti-inflammatory agents. They have pro resolving and tissue
modifying properties that are useful in managing patients with
cardiovascular disease.


Dr Carolyn Lam: Interesting. So what did these authors find?


Dr Greg Hundley: This study showed that human stenotic aortic
valves contain decreased levels of n-3 PUFA, and that n-3 PUFA
treatment decreased aortic valve calcification, and aortic valve
leaflet area in murine models’ concomitant with improved aortic
valve hemodynamics. The pro resolving lipid mediator, resolvin
E1, which is derived from the n-3 PUFA enoic acid, or EPA,
exerted protective effects on valvular interstitial cell
calcification and valvular inflammation through its receptor,
chemR23. And therefore Carolyn, further clinical evaluation of
n-3 PUFA treatment may open up novel therapeutic opportunities
for preventing the progression of aortic valve stenosis.


Dr Carolyn Lam: Wow, really interesting, Greg. Just more and more
data on these omega−3 PUFAs, huh? So cool. Well, the next paper
is kind of related in the lipid world. Do you think treating to a
low LDL cholesterol target of less than 70 milligrams per
deciliter may impact carotid plaque evolution?


Dr Greg Hundley: I would think so. It seems like that target is
beneficial in many ways.


Dr Carolyn Lam: Well, good guess, Greg. But I'm going to tell you
about a study that actually looked at that. First of all, recall
that the treat stroke to target, or TST trial, showed the benefit
of targeting an LDL cholesterol concentration of less than 70 in
terms of reducing the risk of major cardiovascular events in
2,860 patients with ischemic stroke with atherosclerotic stenosis
of the cerebral vasculature. Now, today's paper describes results
of the parallel TST plus study, which included 201 patients
assigned to an LDL cholesterol concentration of less than 70
versus 212 patients assigned to a target of a hundred. To achieve
these goals, investigators led by corresponding author, Dr
Amarenco from Bichat Hospital in Paris, France, allowed
investigators use the statin and dosage of their choice, and
added ezetimibe as needed. After certification of
ultra-sonographers, carotid ultrasound examinations were
performed at baseline and at two, three, and five years, and
blindly analyzed at a central core laboratory.


Dr Greg Hundley: Very nice, Carolyn. So what did they find?


Dr Carolyn Lam: After a median follow-up of 3.1 years, patients
in the lower target group had a similar incidence of newly
diagnosed carotid plaque compared to the higher target group, but
significantly greater regression of carotid atherosclerosis as
measured by the common carotid intima media thickness. So this
really further strengthens the concept that the lower the LDL
cholesterol, the better the clinical and atherosclerosis
outcomes.


Dr Greg Hundley: Very nice, Carolyn. Another study emphasizing
that very important point. Well, Carolyn, my next study comes
from Professor Abdelkarim Sabri from the Temple University School
of Medicine. So studies suggest that cardiac rupture can be
accelerated by thrombolytic therapy, but the relevance of this
risk factor remains controversial. In this study, the authors
analyzed protease activated receptor or PAR4 expression in mouse
hearts with myocardial infarction, and investigated the effects
of PAR4 deletion on cardiac remodeling and function post demise
by echocardiography, quantitative immunohistochemistry, and flow
cytometry.


Dr Carolyn Lam: Oh, okay. What did they find, Greg?


Dr Greg Hundley: Three things. First, PAR4 deficiency leads to
cardiac hemorrhage and increases the rates of cardiac rupture
following chronic myocardial infarction. PAR4 deficiency in
neutrophils, but not in platelets, impairs inflammation
resolution and myocardial healing after myocardial infarction.
And finally, adoptive transfer of neutrophils can be used as a
novel therapy to modulate the inflammatory response and improve
cardiac remodeling and function following myocardial infarction.


Dr Carolyn Lam: Okay, what's the take home message?


Dr Greg Hundley: It's a little tricky. So acute transient
administration of par four inhibitors may provide a new approach
to prevent early inflammation and myocyte loss immediately after
ischemic injury. The keyword is immediately. But importantly,
prolonged P4 inhibition strategies could impair myocardial
healing and increased cardiac hemorrhage and the rates of
myocardial rupture following infarction. PAR4 inhibition
therapies should be limited to the acute phases of the ischemic
and fault, and it should be avoided for the chronic treatment
post myocardial infarction. Really intriguing, Carolyn.


Dr Carolyn Lam: Very nice and elegant results, kind of like yin
and yang, huh?


Dr Greg Hundley: You bet.


Dr Carolyn Lam: All right. Let's sum up with the other papers in
the issue. There's a white paper by Dr Psotka on challenges and
potential improvements to patient access to pharmaceuticals with
examples from cardiology. There's a perspective by Dr Armstrong
comparing the benefit of novel therapies across clinical trials,
and that provides important insights from the VICTORIA trial.
There's an ECG challenge by Dr Chu regarding a young male with
incessantly alternating tachyarrhythmias.


Dr Greg Hundley: Very nice, Carolyn. Well, in my mail bag, I have
an on my mind piece from Dr Jamil Tajik relating to, our
favorite, the art and science of occultation. Well, Carolyn, how
about we get on to that feature article and talk a little bit
more about those little devils, the streptococci?


Dr Carolyn Lam: Yeah, let's go, Greg. Infective endocarditis is
the topic of our feature paper today. Now, we all know it's a
life threatening disease, and despite its relative rarity, it's
still consumes a disproportionate share of healthcare resources,
and its annual mortality is still really high, exceeding 20%.
Now, I think we all recognize that improved outcomes are
critically dependent on a timely diagnosis and early
investigation. The problem is the clinical presentation is less
and less likely that classical textbook presentation, and the
clinical suspicion is often triggered after microbiological
identification of potential causative organisms in the blood. And
while we as a medical community are usually aware of the
dangerous of staphylococcal bacteremia, I think there's a lot
less appreciation of the propensity of different streptococcal
species to cause infective endocarditis. Greg, my dear partner,
greatest friend, and colleague, do you agree?


Dr Greg Hundley: Yes, Carolyn. So this paper and this feature
addresses bacterial endocarditis and focuses on streptococcal
infections just as you've described. Now, streptococci I
frequently cause infective endocarditis. Yet, the prevalence of
infective endocarditis in patients with bloodstream infections
caused by different streptococcal species is unknown. So in this
study, Dr Shamat and associates aim to investigate the prevalence
of infective endocarditis at species level in patients with
streptococcal bloodstream infections.


Dr Carolyn Lam: Now, we're taking a lot of pains to describe this
paper, Greg and I, because we didn't manage to get hold of the
authors this time. We certainly have our editor who managed the
paper and that's Ntobeko Ntusi from University of Cape Town. So
welcome Ntobeko, and thank you so much for discussing this paper
with us. But before we get to that, I think Greg and I are going
to try to, in our usual fashion, get to the bottom of describing.
Here's something I learned that I didn't know before. That the
ESC guidelines for example, are primarily based on the modified
Duke criteria, which include blood cultures, mentioning viridians
streptococci. Remember those? Viridians streptococcus, or strep
bovis, as a diagnostic major criterion for streptococcal
infective endocarditis.


And yet, the term viridians is based on bacterial culture using
green hemolysis on blood agar plates, which is outdated. So I
didn't realize that. It's outdated and inconsistent because some
of the included streptococcal species do not even cause
hemolysis, and other species are able to produce different kinds
of hemolysis. And thus, we really need more details on specific
streptococcal types that are much more current. And when we face
these different streptococcal species, they're not mentioned in
the guidelines and so we need more data. So that's why this paper
is so important. So Greg, now over to you. Do you mind to
describe what the authors did?


Dr Greg Hundley: Sure, Carolyn. So these investigators identified
and assessed all patients with streptococcal bloodstream
infections from the period of time of 2008 to 2017 in the capital
region of Denmark. And data were cross-linked with Danish
nationwide registries for identification of concomitant
hospitalization with infective endocarditis. In multi-variable
logistic regression analyses, the authors investigated the risk
of infective endocarditis according to some of those species that
you just mentioned. And they adjusted their analyses for age,
sex, greater than or equal to three, positive blood culture
bottles, native valve disease, prosthetic valves, prior episodes
of infective endocarditis, and whether or not they may have had
an implanted cardiac device.


Dr Carolyn Lam: Great, great. So tell us the results, Greg.


Dr Greg Hundley: So Carolyn, they had 6,500 plus cases with
streptococcal bloodstream infections. And the average age of the
patients was 68 years, and a little more than half. So 52% to 53%
were men. The prevalence of infective endocarditis overall was
7%. Now, the lowest infective endocarditis prevalence was found
with strep pneumoniae and strep pyogenes, ranging from 1.2% to
1.9%. the highest infective endocarditis prevalence, and that was
found with strep mitis or oralis at 19%. Streptococcus
gallolyticus, formerly known as strep bovis, at 30%. Strep
sanguinis at 35%, and strep mutans at nearly 50%, at 48% overall.
So in multi-variable analysis, using the strep pneumonia at 1.2%
as a reference, all species except strep pyogenes were associated
with a significantly higher infective endocarditis risk. Again,
the highest with the odds ratio of strep gallolyticus is at an
odds ratio of 31 ranging up to straight mutans with an odds ratio
of 81.3.


Dr Carolyn Lam: Whoa, Greg, that was beautifully summarized, and
frankly, beautifully pronounced. I don't think I could have done
that with all the species. That is so cool. And in case everyone
didn't get it, I strongly suggest you refer to figure three of
this beautiful paper. It shows the prevalence of infective
endocarditis in bloodstream infections with the different
streptococcal species, all in one figure. And Ntobeko, with that
introduction, if you may, by both Greg and I, could you please
let us behind the scenes? Tell us what you first thought when
this paper came across your desk and perhaps what the editors’
thought was so important about this paper.


Dr Ntobeko Ntusi: Thank you very much, Carolyn and Greg. So this
is an important paper coming out of circulation. And while
infective endocarditis may not be so harmonic in North America
and western Europe, in many parts of the world, including where I
come from in Sub-Saharan Africa, with a high prevalence of
rheumatic heart disease, it remains an important cause of
morbidity and mortality. And we forget that it's a disease with
very high inpatient mortality of up to 50% in many countries. And
of course in those with rheumatic heart disease, streptococcal
bloodstream infections remain an important cause of infective
endocarditis.


So when I saw this paper, I very much enjoyed reading it. I
thought it was well written and beautifully illustrated. In some
ways, even though I say it's an original paper, it has a feel of
a review because the discussion, as well as the figures and
tables, are quite instructive. And the comments from the
reviewers were very much aligned with my own thinking that there
were a number of important new learnings coming out of this
paper. The first important message for me was that the
distribution of streptococcal infections in the population was
not uniform and I had assumed infections to be broadly the same
across the population. And contrary to what I thought, the risk
of infective endocarditis was inversely related to the frequency
of streptococcal bloodstream infections in the population.


In other words, the most common streptococcal blood infections
that are very low prevalence of infective endocarditis. And that
leads to the second important learning from this paper, which is
that if you are a clinician evaluating a patient with suspected
infective endocarditis, the risk of infective endocarditis should
be evaluated on a species level, as the species from Greg's
description is probably the most important determinant of the
likelihood of developing infection. And then the other important,
I think, take home message from this paper, I'm looking at the
results of multivariate regression analysis, is that it confirms
much of what we know from studies with older patients studies
focusing primarily on staphylococcal bloodstream infections as
well as studies focusing on device therapies.


And that message is that the risk of developing infective
endocarditis, even with streptococcal blood infections is related
down to presence of native or valve disease. Those with trust
that tech devices, intracardiac devices, and of course, the
number of fat blood culture bottles that are positive, which is
something that is well accepted and established in clinical
practice. Thank you, Carolyn.


Dr Carolyn Lam: I just love those three take home messages. So
beautiful. And I really also love that you invited this fantastic
editorial, Dr Prendergast, Dr Allen, and Dr Klein. I thought it
was wonderful the way they summarized the paper, put it into
context, and perhaps, I could borrow their words and also
explaining that they pointed out that we do need to be cautious
about interpreting this being a retrospective series classified
by diagnostic coding. And of course, by design, because of that,
we can't fully attribute causal associations.


They also pointed out that this paper, I believe did not include
echocardiographic data as one of the variables. And so of course,
that could be something that could be further explored in future
studies. And I'd love your thoughts on what they also said about
before we extrapolate regional data, I mean, it's all from
Denmark after all, to other regions, this work should probably be
considered something that should inspire extension of further
studies and prospective evaluations in other areas, and yet never
losing sight of the fact that this informative paper will of
course be of considerable interest to not just cardiologists, but
also infectious disease specialists, because we're often called
to sort of assess, "All right, how much do you need to work up
for infective endocarditis if you see this specific streptococcal
bacteremia?" And this paper definitely puts us strides ahead in
this area. Would you agree with that, Ntobeko, and anything to
add?


Dr Ntobeko Ntusi: Indeed, Carolyn. So I was delighted that the
review, the editorial, was co-authored by cardiologists and
infectious disease specialists. We might view as they balanced in
as one of the modifications to the original submission. We
actually posed that question to the office that how can we be
certain in the absence of echocardiographic data that the
diagnosis was in fact infective endocarditis in patients? And so
they went back and performed a sensitivity analysis and
triangulated the principle diagnosis of infective endocarditis
with the treatment of patients in the duration in hospital. And
that sensitivity analysis in fact strengthened our believe that
this wasn't fit the diagnosis of infective endocarditis. And I
think your point is well taken that similar studies need to be
conducted in different regions of the world and this field will
be strengthened by large amount of prospective studies on top of
the plethora of retrospect data that we have.


Dr Greg Hundley: Well listeners, we have a second feature
discussion this week. A very interesting article pertaining to
the use of smartwatches and detection of atrial fibrillation. And
to present this work, we have Dr Bapu Jena from the Harvard
Medical School, and our own associate editor from University of
Texas Southwestern Medical Center in Dallas, Dr Sandeep Das.
Welcome gentlemen. And Bapu, perhaps, could you tell us a little
bit about the hypothesis and the background of this material?


Dr Anupam B. Jena: Sure. So you probably are aware that in
December of 2018, Apple released this new watch and this watch
made a lot of buzz in part because it featured this single lead
EKG that the company said would be able to detect atrial
fibrillation. And there was this question among many, at least
certainly among clinicians, as to whether or not we would see a
large increase in atrial fibrillation diagnoses after this watch
was released onto the market. And then the second question was,
would we be picking up worrisome cases of atrial fibrillation
that we needed to act on, or would we be picking up cases that
patients probably would have been okay living with and would
never have known that they were living with?


We were lucky to be able to work with a company called
Athenahealth. Athenahealth is a nationwide cloud-based healthcare
information technology company. What that allowed us to do was to
do a very early analysis of the change in atrial fibrillation
diagnosis after the Apple Watch was approved on the market. So
that's the data we use is from small physician practices. It's
not nationally representative, but these practices are all across
the US. The data from Athenahealth have been used in other
studies, including some by myself and other colleagues.


In terms of the method that we applied; it was pretty straight
forward. So what you basically want to see is before and after
December of 2018, do we see a market spike in the diagnosis for
atrial fibrillation? Again, these are diagnoses that physicians
who are in these offices would be making and that we would be
seeing in the electronic health records of their practices. Now,
the problem is, is suppose over time, atrial fibrillation
diagnoses are going up. So if we looked at the first six months
of 2019 compared to the last six months of 2018, and we saw an
increase, we obviously wouldn't want to attribute that solely to
the Apple Watch because atrial fibrillation diagnoses may be
going up for a lot of other reasons. What we said as well, let's
at least try to account for the possibility that there are
seasonal trends at play in the diagnosis of atrial fibrillation.


Dr Greg Hundley: Very nice. What did you find?


Dr Anupam B. Jena: So the basic finding is as follows that we
didn't really see a differential increase in atrial fibrillation
diagnoses. So for example, in the months before the watch was
released, in this population, about 0.4% of all visits had an
atrial fibrillation diagnosis. 0.4%. If you look at the year
after the app release, about 0.4% of visits have the diagnosis.
If you look one year back, you also find that one year before in
the pre period, there is about 0.36% of visits were for atrial
fibrillation, and that increased the 0.39%. So the difference in
difference change is basically about zero. Meaning, we found that
there was no increase in atrial fibrillation diagnoses. The
second thing that we did is we looked at high income zip codes,
and we looked at zip codes with the population of individuals
would be such that we might expect an increase. And we found no
changes in either one of those two subgroups.


Dr Greg Hundley: Very good. Well, Sandeep, help us put this in
the context of using these watches and then also using these
watches to identify patients with atrial fibrillation.


Dr Sandeep Das: Absolutely. So let me first just add a comment
that Bapu was a little too modest to blow his own horn, but he's
really built a lovely research program of identifying and
answering really interesting questions in large datasets. So the
fundamental question here about whether the use of the Apple
Watch and these detection algorithms would be associated with a
big spike in diagnosis of atrial fibrillation was extremely
important or is extremely important. So that was really the hook.
I knew it was going to be something interesting. In our heart of
hearts, we're all a little worried that people are going to have
wearables. There's going to be an 8 million people presenting
with abnormal findings on their watch and it's going to break
medicine. So that was really kind of the context and the key for
what made it interesting to us.


Dr Greg Hundley: Very nice. And so what do you think, maybe start
with Babu, and then come back to Sandeep. What do you think will
be the next study in this area using these devices as they
pertain to patients with atrial fibrillation?


Dr Anupam B. Jena: Yeah. Great question. So I think there's two
things that come to mind. So first is this was really an early
analysis. I do expect that as the Apple Watch grows in popularity
and as other similar such devices get introduced to the market,
that we probably will pick up patients with atrial fibrillation
who otherwise wouldn't have been diagnosed. I think that's less
likely, but would be diagnosed earlier than they otherwise would
have. So I think that if we look a couple of years out, we
probably will find different answers that we found here. But as
Sandeep said, at least in the first year after the watch was
introduced to the market, we didn't break the bank. So I think
this first natural question is to look longer out. And I think
the second thing, which is particularly interesting to me at
least, is that this potentially gives us a nice natural
experiment to understand whether or not all patients with atrial
fibrillation or what are the other factors that we should be
thinking about in terms of benefits?


Dr Greg Hundley: Very good. Sandeep, do you have anything to add?


Dr Sandeep Das: So I agree with that answer entirely. I think
that one of the things that really is going to be the $64,000
question is what does wearable diagnosed atrial fibrillation
mean? So we were pretty good. As Bapu said, we have well
established history of understanding what to do with patients
that have atrial fibrillation that we diagnose in conventional
ways. People either present with symptoms or are diagnosed
externally in the hospital. But what does it mean if you're
perfectly fine and you just have a watch that gives you an alarm?
What are the implications of that? Because there are therapies
generally revolve around anticoagulation in a large fraction of
patients with atrial fibrillation. And that's the big deal.


If we're going to commit people to lifelong anticoagulation,
based on what they're watch told us, is that the right thing to
do? So I think that to me, the most important question going is
what does a diagnosis of a-fib by wearable mean for downstream
treatment implications and outcomes? And then the larger scope is
also how can we then incorporate the data that we're going to
continue to get from wearables into practice? So studies on sort
of the practical downstream implications of wearable technology
on utilization are also going to be super important and
interesting.


Dr Greg Hundley: Very good. Well, I want to thank you Bapu, and
also thanks Sandeep for your time today. And just sharing this
new research using Apple smartwatches and trying to diagnose
atrial fibrillation and compared it at least in this first year
to, I guess, historical controls, not an overabundance or mass
increase in the diagnosis of atrial fibrillation. And as you both
have identified more to come with research on using these watches
in the future for management, and then how we might improve
therapeutic interventions through the use of these devices. Well,
listeners, we hope that you have a great week and we look forward
to catching you on the run next week. Take care. This program is
copyright of the American Heart Association, 2020.