Circulation September 3, 2019 Issue

Dr Carolyn
Lam:               
Welcome to Circulation On The Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
cohosts. 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 from the Pauley Heart
Center at VCU Health in Richmond, Virginia.


Dr Carolyn
Lam:               
So Greg, have you ever wondered what is the clinical significance
of exercise induced cardiac troponin eye release with regards to
mortality and cardiovascular events?


Dr Greg
Hundley:            
Well, being a runner, and you are too, I actually have wondered
about that.


Dr Carolyn
Lam:               
Well guess what? I'm not going to tell you the answer because
you're going to have to wait for our feature discussion coming
right up after we chat about a few wonderful papers in this
week's issue. And I want to start. So the first paper I chose
really sought to discover new and effective drug treatments for
ischemic stroke. And it did this by integrating genetic and
proteomic data through Mendelian randomization analysis.


Dr Greg
Hundley:            
So Carolyn, what is Mendelian randomization analysis?


Dr Carolyn
Lam:               
Well, I would have loved to quiz you on that, but since you
already asked me, I'll tell you. So Mendelian randomization is a
statistical genetics framework that's used to assess causality
between an exposure and an outcome. So similar to how randomized
controlled trials randomly allocate an intervention to test its
causal effect on an outcome. Well, Mendelian randomization
represents a sort of natural randomized control trial that
leverages the random allocation of exposure influencing genetic
alleles.


                                               
Now previously, this technique of Mendelian randomization was
applied in a hypothesis driven manner to assess causality of
selected biomarkers on stroke risk, for example. However, there
has been no systematic scan of the human proteome for novel
causal mediators of stroke. And beyond drug target
prioritization, Mendelian randomization can actually also be
applied to predict target mediated side effects to reveal
unanticipated adverse effects and opportunities for drug
re-purposing. Hence, in the current paper, the authors led by Dr
Paré from Hamilton Health Sciences, McMasters University and
colleagues, use Mendelian randomization to firstly systematically
screen 653 circulating proteins to identify novel mediators of
ischemic stroke subtypes.


                                               
Secondly, examine the relationship between identified biomarkers
and the risk of intracranial bleeding. And thirdly, predict
target mediated side effects through phenome wide analysis. They
found that among these 653 proteins, seven were causal mediators
of ischemic stroke, including two established targets,
apolipoprotein allele and coagulation factor 11. As well as two
novel mediators of cardioembolic stroke, which were scavenger
receptor class A5, or SCARA5, and tumor necrosis factor weak
inducer of apoptosis.


                                               
They further showed that targeting SCARA5 was predicted to also
protect against subarachnoid hemorrhage with no evidence of it
for side effects. Some biomarkers mediate at risk of multiple
non-stroke disorders. So in summary, integrating genomic,
proteomic and phenomic data through Mendelian randomization
facilitated discovery of drug targets and their side effects.
Their findings provide confirmatory evidence for pursuing
clinical trials of coagulation factor 11 and apolipoprotein
allele. Furthermore, SCARA5 represents a new therapeutic target.
Neat, huh?


Dr Greg
Hundley:            
You bet. Well, my basic paper, Dr Carolyn Lam, focuses on the
border zones of infarcts. And it comes to us from Vincent
Christoffels from the Academic Medical Center in Amsterdam. So
surviving cells in the post infarction border zone is subjected
to intense fluctuations of their microenvironment. We can imagine
that. And recently border zone cardiomyocytes have been
specifically implicated in cardiac regeneration. Here in this
study, the investigators define their unique transcriptional and
regulatory properties and comprehensively validated new molecular
markers, including NPB or encoding B-type natiriuretic peptide
after infarction.


                                               
So, in the study, transgenic reporter mice were used to identify
the NPB positive border zone after mitochondrial infarction, and
transcriptome analysis of remote border and infarct zones, and of
purified cardiomyocyte nuclei was performed using some RNA
sequencing. Top candidate genes displaying border zone spatial
specificity were histologically validated in ischemic human
hearts. So like these great papers we have in basic science,
there is a fundamental mouse and then human subject validation.


Dr Carolyn Lam:
               
Nice. A lot of work. So what did they show?


Dr Greg
Hundley:            
So Carolyn, the investigators identified the border zone as a
spatially confined region transcriptionally distinct from remote
myocardium. The transcriptional response of the border zone was
much stronger than that of that remote ventricular wall involving
acute downregulation of mitochondrial oxidative phosphorylation,
fatty acid metabolism, calcium handling and sarcomere function,
and activation of the stress response program.


                                               
Analysis of infarcted human hearts revealed that the
transcriptionally discrete border zone is conserved in humans and
led to the identification of novel conserved border zone markers
including NPBB and a whole list of others. So in conclusion,
cardiomyocytes in a discrete zone bordering the infarct switch
gene expression programs, this post switch program is conserved
between mouse and humans, includes the NPPB expression, which is
required to prevent acute heart failure after infarction.


Dr Carolyn
Lam:               
Wow, really interesting. Well, my next paper is also really just
novel information, and it's a promising clinically-relevant
approach for immune modulation in transplantation medicine. And
that is by selectively targeting notch one.


Dr Greg
Hundley:            
Tell us a little bit about notch signaling.


Dr Carolyn
Lam:               
Well, I'm glad you asked me before I asked you again because
notch signaling is a highly conserved pathway, pivotal to T cell
differentiation and function, rendering it a target of interest
in efforts to manipulate T cell mediated immunity. Now this is
relevant in transplantation since, despite advances in
immunosuppression, long-term outcomes remain suboptimal and is
hampered by drug toxicity and immune mediated injury, the leading
cause of late graph loss.


                                               
So, the development of therapies that promote regulation while
suppressing effector immunity is imperative in improving graph
survival and minimizing conventional immunosuppression. In
today's paper, Dr Riella and colleagues from Brigham and Women's
Hospital, Harvard Medical School in Boston, Massachusetts
investigated the pattern of notch one expression and effector and
regulatory T cells in both murine and human recipients of a solid
organ transplant. They further examine the effect of notch one
receptor inhibition in full murine cardiac and lung transplant
models as well as in a humanized skin transplant model, and also
in T regulatory cells. They found that notch one is a potent
novel target to modulate aloe immunity. Blockade of notch one
signaling prolongs allograph survival and enhances tolerance in
animal transplant models in a regulatory T-cell dependent manner.


                                               
So, in summary, these data suggests that notch one signaling
pathway is a potentially clinically relevant target to control
effector function and promote immune regulation after
transplantation.


Dr Greg
Hundley:            
Oh wow. A lot of intense work, and I learned about notch
pathways. I am going to switch and talk about a clinical
situation that's really emerged over the last five years,
particularly in our scientific literature. And that's tricuspid
regurgitation. And this paper comes to us from Dr Jeroen Bax from
Leiden University Medical Center in the Netherlands. So in
patients with moderate and severe tricuspid regurgitation, the
decision to intervene is often influenced by right ventricular
size and function. And right ventricular remodeling in
significant secondary TR however been under explored. And so in
this study the investigators characterize right ventricular
remodeling in patients with significant secondary tricuspid
regurgitation, and they investigated its prognostic implications.


Dr Carolyn Lam:
               
Indeed, very important topic. So please tell us what they found.


Dr Greg
Hundley:            
Okay, so they use transthoracic echo-cardiography, and it was
performed in 1,292 patients with significant secondary tricuspid
regurgitation with patients having an average or median age of 71
years. Half were men, half were women. They had four patterns of
right ventricular remodeling, and they were defined according to
the presence of RV dilation with the tricuspid annulus of greater
than 40 millimeters and RV systolic dysfunction. So pattern one
was normal RV size and normal RV systolic function. Pattern two
was a dilated RV with preserved systolic function. Pattern three,
normal RV size with systolic dysfunction. Pattern four was a
dilated RV and systolic dysfunction.


                                               
So the primary end point was all caused mortality and event rates
were compared across these four patterns of remodeling. So what
did they show, Dr Carolyn Lam? The five-year survival rate was
significantly worse in patients presenting with either pattern
three or pattern four remodeling compared to pattern one, which
was normal. And they were independently associated with poor
outcome in multivariable analysis. Thus, in patients with
significant secondary tricuspid regurgitation, patients with RV
systolic dysfunction have worse clinical outcomes regardless of
the presence of the magnitude of RV dilation. So really helps us
as we're trying to decide what going to do with that tricuspid
valve and modifying the severity of tricuspid regurgitation. Very
nice work.


Dr Carolyn Lam:
               
Yeah. Very interesting. Now let's get to our feature discussion.


Dr Greg
Hundley:            
You bet.


Dr Carolyn
Lam:               
Our feature discussion today is all about cardiac troponin
increases after endurance exercise. Is it a new marker of
cardiovascular risk? What should we think of it? Is it associated
with cardiovascular events? Now I know many of us has thought of
this many times and we're going to get some beautiful answers
with today's feature paper. I'm so glad to have the corresponding
author, Dr Thijs Eijsvogels, from Radboud Medical Center that's
in Nijmegen. And I also have our associate editor and
editorialist for this paper, Dr Torbjørn Omland from University
of Oslo. So welcome gentlemen, and if I could please start.
Thijs, I think a good place to start would be for you to tell us
about this four-day march of Nijmegen. Tell us about that and how
your study builds on that.


Dr Thijs
Eijsvogels:          
The Nijmegan four-day marches is actually the largest walking
march in the world, so it's hosted every year in July in the
Netherlands, and about 45,000 people walk for four consecutive
days. And this gave us the opportunity to collect some research
data during this great exercise event. What we did over the past
couple of years is that we've collected blood samples and
participants of this Nijmegan marches. We did a before exercise
and also directly after exercise. Within those blood samples we
determined the concentration of cardiac troponin eye, which is a
marker of mitochondrial damage. And what we subsequently did is
that we followed this group of walkers over time and we collected
data about diverse events that occurred, and also whether they
survived or whether they died over time.


Dr Carolyn
Lam:               
Thijs, it's such a clever setup for a study. Now give us some
idea though. We're saying walking for four days; how many
kilometers is covered? And when you say before and after your
troponin sampling, give us an idea of how many hours of walking
that would be. Because I believe you did it only on the first
day, right?


Dr Thijs
Eijsvogels:          
Yeah, that's correct. So the distance that they must cover is
dependent on sex and on age. So for example, if you're a male
older than 50 years old, you can walk 30 kilometers per day, but
then for four days in a row. But if you are a young individual
like me, then you have to cover 50 kilometers per day. So that's
a lot more. Typically, they walk about four to five kilometers
per hour. So that means that if you walk the shorter distances
then you are done within six to seven hours of walking. But if
you walk for a longer period of time, then you need 10, 11, and
sometimes even 12 hours to complete the distance.


Dr Carolyn
Lam:               
Okay, there you heard it everybody. So we've got a stress test of
a mean, I'm reading from your paper, 8.3 hours of walking at
almost 70% of maximum heart rate. So that's really cool. Now
before you go on further too, tell us a little bit about the
population because everybody's wondering, oh no, does this apply
to me?


Dr Thijs
Eijsvogels:          
So the population participating in this walking event, I would
almost say it's about a representation of the general population.
So we have very healthy and very trained individuals. So you
could say athletes. But we also have people with cardiovascular
disease or cardiovascular risk factors. And even obese
individuals. So it's a very mixed population, and it's not like
the typical athlete population that you see at a runner’s event,
for example.


Dr Carolyn
Lam:               
Great. That's important. So now with that backdrop, please tell
us your main findings.


Dr Thijs
Eijsvogels:          
We measured this cardiac troponin and eye concentration, and we
determined the number of individuals that were above the clinical
threshold, which is the 99 percentile. And then we've compared
the event rate. So major at first cardiovascular events and
mortality with those walkers who had a cardiac troponin above the
99 percentile and those below it. And then we found that it was
way higher in the walkers with the high troponin concentration.
So they had an event rate of 27%, whereas the reference group
they only had an event rate of 7%. So that was quite a marked
difference.


Dr Carolyn
Lam:               
That's huge. So first data of its kind and it's so scary because
I think, Torbjørn, as you discussed in your editorial, a lot of
us have sort of excused the rises in troponin that we know have
been reported at the marathons and all that. So how do you put it
all together, Torbjørn? what are your thoughts?


Dr Torbjørn Omland:      So I would just
like to congratulate Dr Eijsvogels with a very interesting
article. And the findings are, as you say, very novel and
significantly enhances our understanding of the prognostic
implications of exercise induced increase in cardiac troponins.
That transient increase in cardiac troponin concentrations may
occur in many circumstances, and it's usually considered to
reflect acute mitochondrial injury. And thus it has been
considered to reflect harmful pathophysiological processes.


                                               
But there has to be in one notable exception and that has been
the rise in cardiac troponin after endurance exercise, which has
commonly been considered a benign phenomenon. But until this
study, definitive data relating post exercise troponin
concentrations, or the magnitude of the cardiac troponin response
following exercise have been lacking. So with Dr Eijsvogels'
study we now have clear data showing that these are associated
with increased risk.


Dr Carolyn
Lam:               
That's amazing. So thank you for that in context. Thijs, do you
agree? I mean that is a beautiful summary, but what is the take
home for listeners? What should we be thinking about now first
pertaining to our own exercise I suppose, but also then how do we
interpret this clinically?


Dr Thijs
Eijsvogels:          
I think that Dr Omland made a great point. So for a long period
of time we thought that it wasn't a benign phenomenon, that
everybody had those increases in cardiac proponents following
exercise and also the pattern that was way different from what we
see in clinical populations. So we thought, it's just a
physiological phenomenon and it doesn't hurt the heart. But
clearly our study now shows that there is an association between
high post-exercise troponin concentrations and clinical outcomes.
So this is an important finding.


                                               
And basically there are two hypothesis I guess that could explain
those findings. So first of all, it could be that participants
with higher troponins have subclinical or underlying disease. And
due to this walking exercise, that could be a stress test for the
heart. And then those with vulnerable hearts, they demonstrate a
greater increase in cardiac troponins. On the other hand, we
should also acknowledge the hypothesis that even though it's
moderate intensity exercise, it could be some damage to
cardiomyocytes. And those individuals with the greatest or the
highest troponin concentrations, they could have more
cardiomyocyte damage compared to individuals with lower troponin
concentrations. And if you then have repetitive exposures to
exercise bouts, it could be harmful in the long run as well.


Dr Carolyn
Lam:               
And so, Torbjørn, you discuss this along with several different
mechanisms by which troponin could be increased. Do you have
anything else to add to that?


Dr Torbjørn Omland:      No, I think
it's very right what the Dr Eijsvogels point out. So on one hand
we can consider this like a stress test. And there are some data
suggesting that that could be the main effect, in that those who
had the higher baseline troponin in the trifocal study also
demonstrated the highest increase. So in one way you could
consider this as a long-term exercise test. Of course that makes
it less applicable in clinical practice. So because we can't have
exercise test that last for so many hours, but I think that
should be an impetus to have more standardized tests that could
be applied to the clinical practice.


Dr Carolyn
Lam:               
There's also a comment that you made about the kind of troponin
tests that we're applying here, that people should understand
that we're using the high sensitivity ones, right? Is that
correct?


Dr Torbjørn Omland:      Actually, it is
not the high sensitivity, but it is a contemporary essay, but it
had quite good sensitivity even though it is not classified as a
high sensitivity test.


Dr Carolyn
Lam:               
Thank you for clarifying that. I know you made a point about
that, that we should know what kind of tests we're talking about.
The other thing is what are the remaining unanswered questions
then? Like you said, we can't do an eight-hour walking test.
Should we be measuring troponins now in our exercise stress?
Which kinds? What time? No, it's not time yet? What are the next
steps? I'd like to hear from both of you, actually.


Dr Thijs
Eijsvogels:          
First of all, indeed it's not possible in clinical practice to do
an eight-hour tests whatsoever. But I think that it could be
interesting to explore that maybe with some small modifications
to current stress tests, if we do it maybe on a little bit lower
intensity. For example, moderate intensity exercise, but we do it
for a fixed amount of time and then collect blood sample to
determine a highly sensitive correct proponents., then maybe also
the Delta, so the increase in proponents could be predictive sign
of underlying disease. Because what you see in studies that have
been published so far is that the duration of most stress test is
too short to induce any substantial changes in aortic troponin
concentrations. So I think if we modified a protocol a little
bit, we can see greater increases in cardiac troponins, and that
could provide us with more information, of course.


Dr Torbjørn Omland:      I completely
agree. And I think like all great studies, this study raises many
new questions, and of course how we should use this clinically is
very important one. And as such Eijsvogels pointed out,
standardized tests will be required. And I think how much the
Delta information we get from measuring the Delta to just the
baseline should be one topic for future studies.


                                               
And then of course we know that the cardiac troponin increase is
a risk factor. But what we also would like to know is whether the
at risk is modifiable in some way. So there are some studies that
have suggested that increasing your physical activity over time
can actually decrease your sort of chronic cardiac troponin
concentration. And it would be interesting to see whether
increased physical activity over time will also reduce the
increase that you observe after a stress test like in Nijmegan
march.


Dr Carolyn
Lam:               
That's such great points. And if I could add too, not to forget
that the study population here, would I be right to say the
majority are middle aged individuals and they do have
cardiovascular risk factors or even prior cardiovascular disease
in a sizeable proportion? So to what extent these findings
generalized to a really, like the young, athletic, competitive,
athletic population? Could you comment on that Thijs?


Dr Thijs
Eijsvogels:          
I think that's a very good point, that we cannot compare this
population where the fit population competing in running events
or cycling events or triathletes or whatsoever. So I think we
definitely need follow up studies that reproduce our findings in
different cohorts with different training modalities, with
different age categories, and so on. So that's definitely a topic
of interest for future studies.


Dr Carolyn
Lam:               
Thank you so much. I mean, you've inspired me on so many levels.
You've been listening to Circulation On The Run. Don't forget to
tune in again next week.


Dr Carolyn Lam:
               
This program is copyright American Heart Association 2019.