Circulation September 4, 2018 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.


                                               
Current guidelines recommend measurement of one of the cardiac
specific isoforms of cardiac troponin complex. However, what's
the utility of combining measurements of troponins I and T in the
early diagnosis of acute myocardial infarction? Well, you have to
wait for our upcoming feature discussion, but it's coming right
up after these summaries.


                                               
The first original paper this week sheds light on the genetic
basis and mechanisms of bicuspid aortic valve, the most common
congenital heart defect in the population. We know that bicuspid
aortic valve is an autosomal dominant trait with variable
expression and incomplete penetrants suggestive of genetic and
environmental modifiers. In the current study, first author Dr
Gharibeh, corresponding author Dr Nemer from University of
Ottawa, and authors of the Bicuspid Aortic Valve Consortium
assessed cardiac structure and function in mice, lacking a GATA6
allele. They found that GATA6 heterozygous mice had a highly
penetrant type of bicuspid aortic valve with right and left
leaflet fusion, which is the most frequent type found in humans.
GATA6 transcript levels were lower in human bicuspid aortic valve
as compared to normal tricuspid valves. Mechanistically, GATA6
haploinsufficiency disrupted valve remodeling and extracellular
matrix composition through dysregulation of the importance in the
molecules including matrix metalloproteinase nine. Cell-specific
inactivation of GATA6 reveal that an essential rule for GATA6 in
secondary heart field myocytes. Thus, the study identifies a new
cellular and molecular mechanism underlying bicuspid aortic
valve.


                                               
In the field of cardiac regeneration, c-Kit positive adult
progenitor cells were initially reported to produce new
cardiomyocytes in the heart. However, more recent genetic
evidence suggests that such events are exceedingly rare. Today's
paper provides insights into this discrepancy and it is from
first author Dr Maliken, corresponding author, Dr Molkentin from
Howard Hughes Medical Institute Cincinnati Children's Hospital
Medical Center. The authors took a novel approach of deleting the
necessary cardiogenic transcription factors, GATA4 and GATA6,
from c-Kit expressing cardiac progenitor cells to determine
whether true de novo cardiomyocyte formation would occur. They
found that deletion of the necessary cardiogenic transcription
factors, GATA4 and GATA6, from these c-Kit+ cardiac progenitor
cells remarkably resulted in greater apparent cardiomyocyte
derivation from the c-Kit+ cells. Deletion of GATA4 from
c-Kit–derived endothelial progenitors altered the integrity of
the endothelial cell network in the heart, resulting in greater
c-Kit+–derived leukocytes entering the heart and fusing with
cardiomyocytes.


                                               
Thus, they demonstrated a new role for GATA4 in endothelial
differentiation, specifically showing for the first time that
GATA4 is essential for vascular development by the c-Kit lineage.
The study shows that leukocyte to cardiomyocyte fusion is the
primary basis for path lineage tracing results, incorrectly
suggesting that c-Kit+ cardiac progenitor cells generated de novo
cardiomyocytes in the heart.


                                               
Lecithin–cholesterol acyltransferase, or LCAT, is the sole enzyme
that esterifies cholesterol in the plasma. Its role in the
supposed protection from atherogenesis remains unclear, because
mutations in LCAT can cause more or less carotid atherosclerosis.
Addressing this conundrum, co-first authors Drs. Oldoni and
Baldassarre, co-corresponding authors Dr Kuivenhoven from
University Medical Center Groningen, Dr Holleboom from Academic
Medical Center Amsterdam, and Dr Calabresi from University of
Milano in Italy hypothesized that genetic mutations causing
complete LCAT deficiency versus partial LCAT deficiency would be
differentially associated with carotid atherosclerosis in
carriers of LCAT mutations. To study this, they looked at 74
heterozygotes for LCAT mutations who are recruited from Italy and
the Netherlands and who were assigned to complete versus partial
LCAT deficiency. These were also compared to 280 controls. Using
carotid intima-media thickness as a measure of atherosclerosis,
the authors demonstrated that carriers of LCAT mutations leading
to complete LCAT deficiency exhibited less carotid
atherosclerosis, indicating a reduced risk of cardiovascular
disease.


                                               
By contrast, however, carriers of LCAT mutations leading to
partial LCAT deficiency showed marginally more atherosclerosis.
The association of mutations in LCAT with subclinical
atherosclerosis appeared to be related to the capacity of LCAT to
esterify cholesterol on apoB-containing lipoproteins since the
abnormal LCAT present in the partial deficiency was only active
on this class of lipoproteins. These important findings bear
relevance for pharmaceutical strategists that target LCAT.


                                               
After a bioprosthesis aortic valve replacement, what is the
incidence, correlates, and outcomes of hemodynamic valve
deterioration? First author Dr Salaun, corresponding author Dr
Pibarot from Quebec Heart and Lung Institute and their colleagues
studied 1,387 patients who underwent bioprosthetic aortic valve
replacement and found that hemodynamic valve deterioration
identified by Doppler echocardiography occurred in one-third of
patients and was associated with a 2.2-fold higher adjusted
mortality. Diabetes and renal insufficiency were associated with
early hemodynamic valve deterioration whereas female sex warfarin
use and stented bioprosthetic valve versus the stentless ones
were associated with late hemodynamic valve deterioration. These
findings suggest that following bioprosthetic valve replacement,
a systematic echocardiographic follow-up may be considered to
ensure adequate detection and quantitation of hemodynamic valve
deterioration.


                                               
That wraps up on the summaries this week. Now for our feature
discussion.


                                               
We are recognizing the critical role that cardiac troponins play
for the early diagnosis of acute myocardial infarction. We also
know that there are different isoforms of cardiac troponins, the
cardiac troponins T and I. Now, have you ever considered
combining the two? How does that help the early diagnosis of
acute myocardial infarction? Well, I am delighted to have with us
the corresponding author of our feature paper today, Dr Christian
Mueller from University Hospital Basel in Switzerland, a very
familiar voice on this podcast. Welcome, Christian, and thank you
so much for publishing yet another wonderful paper with us.


Dr Christian Mueller:      Thank you
very much for highlighting this important work and allowing me to
comment on it in the podcast.


Dr Carolyn
Lam:               
Christian, first of all, could you paint the background to help
us understand what's the difference between the two isoforms, I
mean, in terms of diurnal variation, the way that they may be
released earlier or later, the way they may or may not be
impacted by comorbidities like renal dysfunction or hemolysis?
Could you help us understand why there may be rational to combine
the two in looking at their impact on the diagnosis of acute
myocardial infarction?


Dr Christian Mueller:      The
measurement of cardiac troponin as a structural protein unique to
the heart clear is a central piece in our early diagnosis of
acute myocardial infarction, so both for the early rule out in
patients who present with chest pain and are finally found to
have more benign disease as well as the early ruling. In general,
I think it's important to highlight that there are two isoforms
exactly as you have mentioned, so there is cardiac troponin T and
cardiac troponin I. So these two proteins are cardiac specific
and are used in the diagnosis of acute myocardial infarction. Now
with the development of high-sensitivity methods or measurements
of both cardiac troponin T and cardiac troponin I concentrations,
we have been able to get a little bit of a better understanding
of in fact differences in the pathophysiology as well as
analytical details between cardiac troponin T and I.


                                               
Before I start highlighting the differences, I think it's
important, I mean, both signals show a very strong correlation,
so still very, very similar to each other. However, the small
differences that have begun to emerge kind of allow to suggest
that possible we could use them together as two pieces of
information in the diagnosis.


                                               
So, what are the differences? First, exactly as you have
highlighted, that if in fact that diurnal rhythm with cardiac
troponin T, which means that cardiac troponin T concentrations
are higher in the morning hours as compared to the evening, we
still have no clue why that's the case, but it's a relevant
difference about 25% and it has been shown in two cohorts and a
group from Maastricht who was the first one highlighting this.
This rhythm has not been found for cardiac troponin I. The second
difference is that, again, probably understood in many, many
population studies cardiac troponin T concentrations are even
stronger predictors of death as compared to cardiac troponin I
concentration. Then the third difference it seems that if we
measure it with high-sensitivity assays, for example high
sensitivity, it seems to rise or if you released from injured
cardiomyocytes even slightly earlier as compared to T and
possibly even less injuries necessary to release I as compared to
T.


                                               
Then you mentioned renal function. Cardiac troponin T
concentration shows slightly higher correlation with renal
function as compared to I. Also, other pre-analytical issues,
hemolysis seems to affect T and I concentration in a different
way. So a lot of small tiny differences that have emerged and
that underlie the hypothesis that possibly by combining the two
signals we could be even more accurate in the diagnosis rather
than relying on one on its own.


Dr Carolyn
Lam:               
That's good. That really sets up the rational very well. I think
in and of itself is a learning lesson, because I think most
clinicians sort of take the two equivalently. So could you tell
us what you found?


Dr Christian Mueller:      I would like
to of course thank the fantastic team that has allowed us to
generate this data. It's a collaboration between the APACE
investigators, the ADAPT investigators and experts in clinical
chemistry from Maastricht University and Noreen Fandalin and
Karen Villa of the first office. So we used two large diagnostic
studies, APACE and ADAPT. We measured high-sensitivity cardiac
troponin T and I and both of them and compared the diagnostic
performance as compared to the final adjudicated diagnosis by two
independent cardiologists who, of course, had all information,
cardiac imaging and whatever you need to adjudicate.


                                               
So, what we found is that in general if you look at diagnostic
accuracy, overall is quantified by the area under the curve.
Combining the two signals did not consistently increase overall
diagnostic accuracy as compared to the individual isoforms.
However, we were able to document some improvement for the rule
out for the very early rule out of acute myocardial infarction.
So the concept that is extremely attractive of course from a
medical as well as from an economic perspective is to rule out
the presence of acute myocardial infarction with a single blood
draw. So, we can do this if we assess the ECG. The ECG doesn't
show relevant changes. Then if the troponin concentration
measured with a high-sensitivity assay is very low, then the
likelihood that the patient would have an acute myocardial
infarction again is extremely low or in scientific term sort of a
negative predictive value approach is 99 to 100%. By combining
very low concentration for high-sensitivity T and very low
concentration for I, we were able to increase the efficacy of the
early rule out and that seemed to be the most likely possible
clinical utility of combining the two signals.


Dr Carolyn
Lam:               
Even that so-called neutral findings are very important. It's an
important question to ask and important answer to get. Could you
give us an idea for the rule-out part? How much do we gain? How
much exactly do we gain by using both assays instead of just one?


Dr Christian Mueller:      So, the
efficacy of the early rule-out depends to some extent on the
assay used and the cut off applied. So the current you see
algorithm uses cut-off that has been shown to be very safe.
However, they are regarding their efficacy not very high. So the
current you see recommended cut-offs and approach, allows the
rule-out only in about perhaps 10 or 15% of patients. That number
can be significantly increased, likely doubled or perhaps even
increased threefold by using the combination approach. So this
has been consistently showed both in the derivation and the
validation cohort.


Dr Carolyn
Lam:               
Yeah. Do you think this is ready for prime time? I noticed a very
balanced discussion actually calling for future studies, but
perhaps you could state it better now.


Dr Christian Mueller:      The main
limitation regarding prime time is the fact that currently
manufacturers either of a high-sensitivity TSA or of a
high-sensitivity high method, which means that the vast majority
of hospitals at this point in time do only have one method
available. It would require quite substantial investment in both
hardware as well as changing of the logistics in the lab to
implement measurement of both assays. So I think it's likely
feasible, but it would be associated with relevant investment
from a hospital perspective. In addition, I mean, also the
rule-out approaches that use of only one assay also there are
studies ongoing in trying to further increase the efficacy of the
single marker approach. So I think it's the best tool marker
strategy that we were able to come up with recently, because many
of the other biomarkers that we had tested really didn't work
out. Still, as you mentioned, I think it's also important to be
very, very honest that it will be difficult to implement tomorrow
in most institutions.


Dr Carolyn
Lam:               
Yeah, and perhaps a little bit more work needs to be done to sort
first identify perhaps special situations where these may be
particularly helpful. I supposed like you just said when we're
thinking of the ESCs to review one-hour type algorithm, who knows
maybe we should be having that extra insurance of the second test
in those that test it negative in the first or something like
that. Do you plan further work? I always ask you because you're
always in the forefront of these things and we just love touching
your work.


Dr Christian Mueller:      We have
several additional analyses ongoing. Again, I think the main part
is for just to go ... I go back from a clinical perspective. So I
think for many hospitals that are using T at the moment, it's
important to have I available for certain situations. So for
example if you have a patient in whom you have evidence of
chronic skeletal muscle disease, most of these disorders are rare
but some of them have been shown to be associated with
increasingly highly troponin T that do not seemed to be related
for cardiac diseases but from skeletal muscle. This is rare but
if you have a patient with that kind of history, then the dual
mark measurement is I think mandatory.


                                               
The same applies to iso that the other reasons to have false
positive results for iso whenever you are ... If your hospital is
using I, you should have the T method also available because once
in a while you will identify patients in whom you have an I
result that doesn't really match the clinical setting, then it's
so easy and often so helpful to get the T result to decide on the
most appropriate measurement of patient.


                                               
For which patients are kind of a standard that measures T and I
would be justified, I think that's something to tease out in
future study. I think that the rational is there and likely it
will depend also on kind of which T or which I method we might
use in the future. So at the moment, we have one method for
high-sensitivity T, but there are several other methods in
development and kind of applying for FDA approval for
high-sensitivity I and possibly combination of these might be
even more beneficial regarding the single measurements and I
think that has to be teased out in future studies.


Dr Carolyn
Lam:               
Exactly, but what great insights for us to consider as clinicians
now for specific cases where we may consider find those if we
have those in our institutions. At the end of the day, I supposed
cost-effectiveness analysis will need to be done. Agree?


Dr Christian Mueller:      Absolutely,
absolutely. The good thing about troponin, it's extremely
inexpensive. So as compared to most of the new fancy biomarkers
that are usually, rather prices of troponin is a routine marker.
It's inexpensive. It's there for very likely that if we are able
to document some clinical value that also the cost-effectiveness
study that's definitely unnecessary will show also some economic
benefit.


Dr Carolyn
Lam:               
Oh, Christian, thank you for publishing yet another impactful and
clinically relevant paper with us here in Circulation. I mean,
it's exactly the kinds of papers that we really treasure here,
because they directly inform clinicians and open our eyes to
actually things that we should be considering in our everyday
practice. Clod I ask you maybe cheekily to share about your
experience with publishing at Circulation? Someone like you will
be the best person to tell the world what it's like.


Dr Christian Mueller:      Oh, of
course. I mean, for us as a research group and for me as a
researcher, it's fantastic. It's perfect to have some of our work
published in Circulation that has fantastic impact factor,
fantastic readership and ensures that the research catch the
attention that's fantastic. Also, I think for us as a research
group, the recognition of being able to publish in Circulation is
outstanding and it helps us continue in the research group that
we do. The comments made to large extent also by the editors.
Also, on this manuscript, I think we're incredibly insightful and
definitely had a major contribution to the final product to make
it as attractive and also as balanced and insightful I think as
it is at this point in time.


Dr Carolyn
Lam:               
Thank you so much for providing that feedback, because it is our
aim, explicit aim to put a partner authors in getting the best of
the manuscript and working really closely with you. So thank you
once again, Christian, for your time today. Audience, I know
you've heard many times from this favorite person that we have on
our podcast.


                                               
Do share this podcast with all your colleagues and don't forget
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