Circulation January 21, 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 Carolyn Lam, Associate Editor from National Heart
Center at Duke National University of Singapore.


Dr. Greg Hundley: And I'm Greg Hundley, Associate Editor,
Director of the Pauley Heart Center in Richmond, Virginia.


Dr. Carolyn Lam: Greg, it is so good to be back. I just love
doing these podcasts with you and what more when we get to
feature a paper like the one that we have this week. It's all
about high sensitivity, cardiac troponin and the universal
definition of myocardial infarction, one of these evergreen
topics that we truly need to understand better. But before we go
onto that, I want to share my first paper. It's a preclinical
paper and it provides an important breakthrough discovery that
could protect the heart against progressive left ventricular
systolic dysfunction following injury. Want to hear about it?


Dr. Greg Hundley: Absolutely.


Dr. Carolyn Lam: Okay. It's from course wanting authors, Drs
Sabourin and Benitah from INSERM University, Paris, as well as
Doctors Foster and Beech from University of Leeds.


Dr. Carolyn Lam: Now, whereas store operated calcium entry has
recently gained attention in cardiac pathophysiology, the role of
the prototypic store operated channel known as Orai1 remains
elusive. So these authors used a novel genetically modified mouse
that specifically disrupts the Orai1 channel in cardiomyocytes
and showed that functional inhibition of Orai1 preserved
alterations of calcium homeostasis, fibrosis and systolic
function without affecting hypertrophy. A novel in vivo small
molecule Orai1 channel inhibitor, in fact, markedly improve left
ventricular systolic function and calcium handling after pressure
overload without causing adverse effects.


Dr. Greg Hundley: Tell me, how does this help me as a clinician?


Dr. Carolyn Lam: All right, you always ask the tough questions.
Well, these results really suggest that Orai1 inhibition has the
potential for favorable hemodynamic value in the protection of
the heart from maladaptive hypotrophy, and therefore might
represent a new way to provide inotropic support to help relieve
systolic dysfunction.


Dr. Greg Hundley: Very good. Well Carolyn, my first paper is from
Dr Peter Kudenchuk from University of Washington Medical Center
and this study evaluates the overall survivor after out of
hospital cardiac arrest from shock refractory ventricular
fibrillation or pulseless ventricular tachycardia related to the
route of accessory drug administration. So to accomplish this,
the investigators had 2,358 individuals that had received
Amiodarone, lidocaine or placebo study drugs and randomized to an
IV route.


Dr. Greg Hundley: And then they also included 661 patients that
received the same medications, but they were randomized to an
intraosseous route.


Dr. Carolyn Lam: So what were the results, Greg?


Dr. Greg Hundley: Well, Carolyn, while no significant effect
modification by drug administration route was observed point
estimates for the effects of both drugs, both the lidocaine and
the Amiodarone, compared to placebo were greater for the IV, as
opposed to the intraosseous route and that was across all
outcomes. And they had significant increases in survival to
hospital admission and discharge and favored improved
neurological outcomes with the IV administration.


Dr. Greg Hundley: Unfortunately, however, the study was
underpowered to examine for an interaction between the route of
vascular access and drug effectiveness and thus additional
studies are needed to determine whether Amiodarone in lidocaine
may be lifesaving drugs in patients with shock refractory out of
hospital cardiac arrest when given IV, but not necessarily
intraosseous.


Dr. Carolyn Lam: Very interesting. Well, my next paper is really
focused on HIV infection and asks the question, is HIV infection
associated with abnormal cardiac repolarization that may
contribute to a greater risk for sudden arrhythmic death? Well,
corresponding author Wendy Post, our very own from Johns Hopkins
University School of Medicine and her colleagues studied 1,123
men, 589 of whom were HIV positive and they were from the
multicenter AIDS cohort study and they were studied using the
ZioXT ambulatory ECG patch.


Dr. Greg Hundley: Wow. Carolyn, this study sounds like it's the
largest study of QT variability in HIV today.


Dr. Greg Hundley: Is that right? And what did the authors find?


Dr. Carolyn Lam: Yeah, it's right. It's huge. And basically they
found that HIV positive men had greater beat to beat variability
in the QT interval compared to HIV negative men, especially in
the setting of HIV viremia and heightened inflammation.


Dr. Carolyn Lam: Among HIV positive men, a higher QT interval
variability suggests ventricular repolarization lability which
could increase susceptibility to arrhythmias. However, lower
heart rate variability also may signal a component of autonomic
dysfunction.


Dr. Greg Hundley: Ah, Carolyn. My next paper goes back to the
world of basic science and it's from Dr. Chen Yan from University
of Rochester. And in this study, Dr. Yon and colleagues examine
the role of cyclic nucleotide phosphodiesterase in isolated adult
mouse cardiomyocytes and fibroblasts as well as in preclinical
mouse models of hypertrophy and/or heart failure. And they found
that phosphodiesterase 10A expression is significantly induced in
mouse and human failing hearts.


Dr. Greg Hundley: It directly promotes cardiomyocyte hypertrophic
growth as well as cardio fiber-blast activation, proliferation,
migration and extracellular matrix production. In addition,
phosphodiesterase 10A deficiency, so not as much of it,
ameliorates cardiac hypertrophy fibrosis and/or dysfunction in
different preclinical mouse cardiac disease models. And finally
inhibiting phosphodiesterase 10A activity with a compound labeled
T P 10 effectively antagonizes the pathological cardiac
remodeling in LVH.


Dr. Carolyn Lam: Huh, that's interesting Greg. And now I'll ask
you, so what are the clinical implications?


Dr. Greg Hundley: Well, phosphodiesterase 10A inhibitors have
been evaluated in phase two clinical trials for treatment of
schizophrenia, suggesting that these agents are safe, druggable,
if you will, targets. And therefore the results with TP 10
suggests a potential therapeutic effect of targeting
phosphodiesterase 10A on antagonizing the development of
pathological cardiac remodeling. Perhaps as suggested by Dr.
Ezekowitz last week, this could represent another new agent in
the treatment of the adverse effects of heart failure syndromes,
more pharmacological agents coming to treat heart failure.


Dr. Carolyn Lam: Wow. That is interesting. But okay, let's talk
about what else is in this issue. So let me tell you about an
online mine by Dr. Kalra and it's called the Cardiovascular
Science India Tour. And what this talks about is a multi-pronged
initiative bringing together professionals and diverse expertise
to allow better understanding of the issues driving the
ever-rising cardiovascular disease burden in South Asia.


Dr. Greg Hundley: Oh, very good. And from the mailbag, I've got a
research letter, Carolyn from Dr. Julian Luetkens from the
University of Bond, who investigates a surrogate of frailty by
examining the fat fraction within skeletal muscle at the L three
L four level. So it's from an axial CT that's acquired at the
time of CT scanning for TAVR pre-evaluation and uses the fat
muscle fraction to forecast TAVR outcomes. Well. Carolyn, that's
a great wrap up. How about we get onto our feature article?


Dr. Carolyn Lam: You bet.


Dr. Amit Khera: Hi, this is Amit Khera. I am digital strategies
editor for circulation and today with our featured podcast we
have Dr. Andrew Chapman from the university of Edinburgh, UK who
is the first author of a study entitled high sensitivity cardiac
proponent and the universal definition of myocardial infarction.
Welcome Dr. Chapman. Thanks for joining us.


Dr. Andrew Chapman: Good morning. It's a pleasure. Thank you.


Dr. Amit Khera: This is obviously a very interesting study and
timely and on the backs of the prior work that your group has
published. Maybe we can start by you telling us a little bit
about the impetus, the background which led to this work.


Dr. Andrew Chapman: We've been using high sensitivity cardiac
troponin in Europe now for some years, and the way that we
diagnose myocardial infarction has, of course changed. We now
recognize that myocardial infarction can occur in the context of
an occluded coronary artery, be that a STEMI or an NSTEMI, also
known as a type one myocardial infarction.


Dr. Andrew Chapman: But increasingly with the use of more
sensitive cardiac troponin, we're recognizing myocardial
infarction can occur in other conditions. So for example, after
arrhythmia or after severe infection with hypoxia. So the real
rationale and background for this study is trying to understand
better the different subtypes of myocardial infarction. As
proposed in the universal definition.


Dr. Andrew Chapman: And we were in quite a unique position to
evaluate this as, when we implemented high sensitivity cardiac
troponin testing in Scotland as part of a randomized controlled
trial. We did so across different hospitals and two of our major
cities, Edinburgh and Glasgow, and the trial which formed the
basis for this study was called the high States trial and we
enrolled 48,000 patients of who we initially used a contemporary
sensitive cardiac troponin on an IRC and we then implemented a
high sensitivity cardiac troponin IRC.


Dr. Andrew Chapman: And that allowed us to evaluate what impact
implementing this high sensitivity test hard firstly on the
prevalence of different subtypes in myocardial infarction, but
also on the investigations and the treatments received. And
finally of course the clinical outcomes of these patients.


Dr. Amit Khera: So obviously at a really sizable study and good
forethought on your group to implement this as this step wedge
type study design. As you pointed out, the goal here was to
understand the different subgroups of myocardial infarction, the
prevalence and implications. Tell us a little bit about what you
found in this study.


Dr. Andrew Chapman: As I mentioned, we had over 48,000
consecutive patients and that was the real benefit of this step
wedge design is that rather than recruiting patients between say
nine and five where we had research nurses available, we enrolled
all consecutive patients. So we think this is quite a
representative population for our area. So of those patients, we
found around 10,000 had elevation in the high sensitivity cardiac
troponin concentration, and we adjudicated these diagnoses in
parallel. So two independent clinicians look through every case,
all the clinical information. And we had a consensus from a third
when there was disagreement. So in short we found that around
half of all elevations in cardiac troponin in this study were to
take one myocardial infarction, that is that the blocked artery
phenotype and the type two myocardial infarctions or an acute or
chronic myocardial injury and myocardial injury being elevation
and cardiac troponin, either acute with a rise or fall or chronic
with a stable concentration with no evidence of myocardial
ischemia and occurred in the other 50% of patients.


Dr. Andrew Chapman: So looking between the phases of the study,
we found introducing high sensitivity troponin disproportionately
increased the diagnosis of Type II MI or acute or chronic
myocardial injury. So there's just an 11% increase in the
diagnosis of Type I MI, and I think again that's highlighting
that these more sensitive tests are finding myocardial damage in
areas that previously it might not have been recognized.


Dr. Andrew Chapman: So moving forward from that, we evaluated the
primary outcome of the trial, which was future myocardial
infarction or cardiovascular death by subgroup. And we also
evaluated unimportant non-cardiovascular death. If I may for just
30 seconds, I'll just discuss why this is important.


Dr. Andrew Chapman: So evaluating future cardiovascular events is
very important and in different subgroups of myocardial
infarction. However, we know patients with Type II MI and acute
or chronic myocardial injury are different. So they tend to be
older, they're more commonly female, they have more
comorbidities, they're on more medications to start with.


Dr. Andrew Chapman: And these patients are ar increased risk of a
competing events to cardiovascular death or a myocardial
infarction. And that is that these patients can go on and die,
will primarily from their primary illness, be an infection or a
pulmonary embolism or what have you. But also they are at
increased risk of death from other non-cardiovascular causes.


Dr. Andrew Chapman: So in this study we were able to evaluate
future cardiovascular risks using quite advanced competing risks
modeling. And I was very grateful for the input of a number of
experts and we managed to find that actually, Type I myocardial
infarction patients with occlusion or partial occlusion of the
coronary artery were at the highest risk of cardiovascular events
going forward.


Dr. Andrew Chapman: But interestingly, even despite the vast
excess in non-cardiovascular death, patients with Type II MI, and
acute or chronic injury also had quite a high cardiovascular risk
over three folds out of patients without myocardial injury. And
we noticed that these patients did not stand to receive increases
in investigations or treatments for coronary heart disease and we
speculate and we hypothesize that actually in a proportion of
these patients there is some clinical coronary artery disease
which has manifested itself during this physiological stress test
of an alternative illness. We wonder and we hope that moving
forward this might be an opportunity for better targeting it in
an investigation and perhaps even improving clinical outcomes.


Dr. Amit Khera: Well, you just shared a ton of important findings
there and I'm going to unpackage a few of them. I guess the first
is this sort of type I versus type II MI, and I think one of the
fears with implementing these high sensitivity troponin would be
perhaps an explosion in these type II MIs. And I think, if you
look, although you mentioned proportionally, the absolute numbers
of increase in type I and type II MI was relatively small so it
didn't seem we had this explosion that I think people had feared
was implementation.


Dr. Andrew Chapman: Yes, that's a fair point. And also need to
bear in mind this is a population of patients from Scotland and
our high sensitivity troponin testing is quite selective. You
would find differences in the impact of high sensitivity if
you're testing practices were different and I know there's prior
work from the United States showing that less selective testing
or to put it in a different way, testing troponin in more
patients. Perhaps some of them may not have symptoms of chest
pain or symptoms suggestive of myocardial infarction, is likely
to change the prevalence of these different groups and you are
likely to pick up more secondary injury or type II MI, but I
think we don't need to panic. There's no need for alarm. I don't
think there is going to be an explosion in recognition of these
patients. If you check a temperature, you'll find a fever, but
provided we're sensible and who we're testing, then I don't think
practice needs to change dramatically.


Dr. Amit Khera: That was a great way to say it. Unfortunately,
we're always looking for fevers in the U.S. So as you pointed
out, the prevalence increase may increase a bit, but definitely
reassuring from what you're finding in your population was more
judicious testing.


Dr. Amit Khera: The second point that you brought up was the
event rates, type I versus type II MI. I guess this does remind
us again that patients with type II have almost comparable
cardiovascular deaths and MI rates as type I, so certainly a
higher risk group. As you pointed out, there's many comorbidities
there and this gets to your point about treatments. I guess the
question is now the event rates are higher, these are higher risk
group or what to do about it I think is one of the vexing
problems. As you pointed out, there's, there's not a lot of
secondary prevention treatments, but what should those treatments
be and where do we go from here in terms of these type II MI?


Dr. Andrew Chapman: That's the million dollar question I suppose
and something that we've explored in another recent circulation
review under the [00:17:07] lead author is what we do for these
patients. When we've looked at different strategies, it seems the
most reasonable initial approach is determining, does my patient
with type II MI or myocardial injury actually have a cardiac
problem?


Dr. Andrew Chapman: Now I don't think we have the evidence to
support routine and baited testing in this population yet and
indeed that might expose patients to harm and that's one of the
tensions with this diagnosis.


Dr. Andrew Chapman: For example, consider the patient with
gastrointestinal hemorrhage and could it have gone forward for an
angiogram. Giving them heparin might not be the best thing to do
in their acute illness. However, whether or not these patients
would benefit from noninvasive tests such as a CT scan to
delineate the coronary anatomy and identify those that might
benefit from an iron platelet agent or a statin or indeed an
echocardiogram to determine which patients have left ventricular
impairment and could benefit from the many number of treatments
we have now for LV impairment and that would be my initial
thinking is that we need to firstly risk profile these patients.


Dr. Andrew Chapman: What is their pretest probability or
likelihood of coronary artery disease? It's not intermediate or
high. Let's have a think about investigating their coronary
arteries. In the first instance, I think a noninvasive test is
going to be most appropriate for the majority of people, but we
need a personalized approach. It may be that someone's just had a
very brief run of an arrhythmia and that's resulted in a
disproportionate level of ischemia and a very high cardiac
troponin.


Dr. Andrew Chapman: Your index of suspicion for that patient
having coronary disease is going to be significantly higher. So a
personalized approach, I think, is where we're heading. And there
are trials which are coming in this area. So yeah, two trial is
being led by Derek Chu of Melbourne in Australia and they're
evaluating the use of CT or invasive angiography to identify
coronary disease and target treatment to see if that can improve
outcomes.


Dr. Andrew Chapman: And certainly here in Scotland, we're hoping
to evaluate the use of a personalized approach to target
treatment in patients with type II MI and again, try and improve
cardiovascular outcomes. So things are coming.


Dr. Amit Khera: Well, I appreciate that and I think as you
pointed out, as we wait for these additional data and additional
studies, sort of a thoughtful. algorithmic approach would be
helpful and we certainly will make sure the readers and listeners
look out for that paper that you mentioned in circulation.


Dr. Amit Khera: I should also point out that your paper here is
an excellent editorial by David Morrow, which has a nice figure
and illustration of your central findings. So we appreciate that.
As we wrap up here, maybe you can tell us what are the main take
homes? What should they take away from this study?


Dr. Andrew Chapman: What we've shown is that high sensitivity
troponin are useful and we've shown that they increase
recognition of patients who have myocardial jury or type II
myocardial infarction, where in the past this may not have been
found and we've shown quite clearly that these are prognostic.
Not only predicting non-cardiovascular disease, but also going on
to identify patients at increased risk of myocardial infarction,
cardiovascular death.


Dr. Andrew Chapman: So I think moving forward, clinicians using
these tests and identifying these patients should be considering
investigations to identify coronary or structural heart disease.
And until we have that high quality randomized controlled trial
data, we need to be pragmatic and we need to evaluate secondary
prevention on an individual patient basis, be that an
antiplatelet agent or be that a statin as the primary ones. This
may even go on to include an ACE inhibitor or a beta blocker if
there's LV impairment, but our aim ultimately has to be to try
and reduce the cardiovascular event rates in this population who,
to date, have been under investigated and undertreated.


Dr. Amit Khera: That summarizes it quite well. And I want to
thank Dr. Andrew Chapman for his excellent discussion today and
that's why we do these backstage passes to get an inside look as
to what the authors were thinking and some behind the scenes on
their papers.


Dr. Amit Khera: Again, I'm Omnicare digital strategies editor for
circulation, and thank you for joining us on this circulation on
the run podcast.


Dr. Greg Hundley: This program is copyright, the American heart
association 2020.