Circulation March 20, 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 Centre and
Duke National University of Singapore. How common is
perioperative myocardial injury after non-cardiac surgery, and
what is its significance? A very important question and a very
important feature discussion coming right up after these
summaries.


                                               
Our first original paper this week tells us that risk assessment
using only non-laboratory based risk factors may be a useful
alternative in the absence of informational lipids, in predicting
adolescents at risk of developing pre-clinical atherosclerosis.


                                               
First and corresponding author, Dr. Koskinen from University of
Turku Finland and colleagues, studied almost 2,900 participants,
age 12-18 years, from four longitudinal cohort studies from the
United States, Australia, and Finland, and followed these
adolescents into adulthood. When carotid intima media thickness
was measured, a mean followup of 23 years later. Non-laboratory
based risk factors such as age, blood pressure, body mass index,
and lipids measured in adolescence, independently predicted high
carotid intima media thickness in young adulthood. The addition
of lipid measurements to these traditional clinic based risk
factor assessments provided a statistically significant but
clinically modest improvement on adolescent prediction of high
carotid intima media thickness in adulthood.


                                               
The next study demonstrates the feasibility of large scale
aptamer multiplexing at a level that has not previously been
reported and with sample proof that greatly exceeds other
existing proteomic methods.


                                               
Now, like antibodies, DNA aptamers can be generated as affinity
reagents for proteins. Emerging data suggests that they can be
used to measure blood protein levels in clinical cohorts.
However, the technology has, to date, remained in its infancy. In
today's study, co-first authors, Dr. Jacob and Dr. Ngo,
co-corresponding authors, Dr. Jennings and Gerszten, from Beth
Israel Deaconess Medical Center in Boston, tested the scalability
of a highly multiplexed expended proteomic technique that uses
single stranded DNA aptamers to assay human proteins with a
markedly expended platform containing approximately 5,000
aptamers targeting a far broader range of analytes than
previously examined using this technology. They applied the
platform to a cohort of individuals undergoing septal alcohol
ablation for hypertrophic cardiomyopathy, using this as a human
model of planned myocardial injury.


                                               
Now, in addition to confirming findings from prior studies, they
identified nearly 150 additional putative markers of myocardial
injury. Thus, these findings suggest that the expanded aptamer
based proteomic platform may provide a unique opportunity for
biomarker and pathway discovery following myocardial injury.


                                               
The next study addresses the potential long-term effects of low
LDL cholesterol on neurocognitive impairment and decline. This
has been a concern with pharmacologic PCSK9 inhibition. The first
author, Dr. Mefford, corresponding author, Dr. Levitan from
University of Alabama at Birmingham, investigated the association
between PCSK9 loss of function variants and neurocognitive
impairment and decline in the regards study.


                                               
In this general population sample of African American adults,
they found no association between PCSK9 loss of function variants
and neurocognitive impairment or longitudinal neurocognitive
decline. There was also no association between lower LDL
cholesterol levels and neurocognitive impairment or decline
during follow-up.


                                               
The study, therefore, provides evidence in a contemporary
population that PCSK9 loss of function variants and resulting
lifelong exposure to low LDL cholesterol levels are not
associated neurocognitive impairment or decline.


                                               
The final study explores long-term outcomes in patients with Type
2 myocardial infarction and injury. First and corresponding
author, Dr. Chapman from University of Edinburgh and his
colleagues identified more than 2,000 consecutive patients with
elevated cardiac troponin I concentrations at a tertiary cardiac
center. All diagnoses were adjudicated as per the universal
definition of myocardial infarction. They found that at five
years, all cause death rates were higher in those with type 2
myocardial infarction or injury compared with type 1.


                                               
Although the majority of excess deaths with type 2 myocardial
infarction or injury were due to non-cardiovascular causes, the
observed crude major at-risk cardiovascular events are MACE rates
were similar between groups. Coronary heart disease wan an
independent predictor of MACE in those with type 2 myocardial
infarction or injury. Thus, despite an excess in
non-cardiovascular death, patients with type 2 myocardial
infarction or injury have a similar crude rate of major at-risk
cardiovascular events to those with type 1 myocardial infarction.
Identifying underlying coronary heart disease in this vulnerable
population may help target therapies that could modify future
risks.


                                               
That wraps it up for our summaries. Now, for our feature
discussion.


                                               
So, I'm gonna go back to my first question on this podcast. How
common is perioperative myocardial injury after non-cardiac
surgery and what is its significance? Well, to give us an answer,
I am delighted to have the first and corresponding author of
today's feature paper, Dr. Christian Mueller from University of
Basel in Switzerland, and we also have Dr. Torbjorn Omland, and
he is associate editor form University of Oslo in Norway. Now, in
case you're having deja vu, you are right. I have had these
gentlemen on this podcast before and they were so successful, I
had to call them back. So, welcome, welcome Torbjorn and
Christian. Thank you for coming back again. Christian,
congratulations on another beautiful paper. Could you tell us the
highlights of what you did and what you found, but this time in
particular tell us the novel aspects in view of the previously
published vision study that was just published last year. Maybe
you could just point out some of the differences.


Dr Christian Mueller:      The topic is
about an interdisciplinary topic and something, I think that is
so important for us as cardiologists to get involved in with much
more detail in the future. So, we are aware of acute myocardial
infarction, sustained myocardial infarction event that we have
studied extensively for decades and for which I think we have a
fuller understanding of its cardiophysiology and we have
excellent treatments. Completely novel entity is perioperative
myocardial injury, so cardiomyocytes that die in the context of
non-cardiac surgery. It's something that we as cardiologists
should be really focused on because its likely the most important
contributor to death in the perioperative period. So, the death
rate among non-cardiac surgery is despite improvements in
anesthesia and surgery remains remarkably high, between 1 and 4%
within 30 days, depending on patient characteristics and surgical
directives. And, it seems from our current understanding that the
heart really plays a major role, rather high percentage of these
deaths.


                                               
So, what is new in our study? Overall, our study took advantage
of insight gained in the first phase of the vision study in that
its has been documented that this perioperative myocardial injury
fairly commonly occur without the patient or we as physicians
getting aware of it. Either because the patient is still having
anesthesia or because he may have symptoms that are atypical. So,
we can only reliably detect this event if we screen an
appropriate population, and that's what we have done. So, I think
the criteria where a patient that's at higher risk of
cardiovascular complication is defined at an age of 65 or higher
or having pre-existing cardiovascular disease. So, this is the
first major difference in which also much younger patients were
enrolled. That's the most important differentiate as we had an
open label screening. So, the screening was part of clinical
routine and it was fine tuned to patients of whom we thought may
have a reasonable high risk of developing this complication.


Dr Carolyn
Lam:               
And, your main findings, because they were striking.


Dr Christian Mueller:      As our most
important finding, we were able to report the incidence of how
many patients actually have a relevant amount of cardiomyocytes
dying during the operation, and it was one out of seven patients
entering our study. So, an incredible high incidence of this
complication and that this complication not only is a very good
end point that you shouldn't care too much was highlighted again
and in full agreement, the suspicious is that if patients develop
this complication of perioperative myocardial injury, their risk
factor of whether they have any symptoms or atypical ischemic
symptoms, and again, only a small minority had the risk of dying
both within 30 days as well as in one year, was substantially
increased.


Dr Carolyn
Lam:               
Christian, before you go on, could you just please clarify, how
did you define perioperative myocardial injury in this case, and
was it the same as the definition used in Vision?


Dr Christian Mueller:      The
perioperative myocardial injury concept initially in Vision it
was defined as detecting an elevated troponin just after a
non-cardiac surgery, and why this was a perhaps an appropriate
definition at the time when we were still using very poorly
sensitive troponin assays inevitably is no longer appropriate
nowadays because its obvious that particularly elderly patients
may have chronic elevations and high sensitive troponin usually.
Mild elevations due to a variety of disorders and [inaudible
00:11:51] important studies for us to understand that it is mild
elevations troponin is quite common in patients with heart
failure, with coronary artery disease or hypertensive heart
disease, whatever. So, if we could detect or start detecting
likely elevated troponin only after operation, we would never
know whether this is something related to the operation itself or
whether it's perhaps had already been around for months and weeks
and represents the chronic condition. So, the novel concept is
that we have to identify an acute rise in troponin, a dynamic
genetics or just like that requested for the universal definition
of myocardial infarction also of course [inaudible 00:12:32] So,
we requested in this study, an increase from the concentration
prior to surgery of at least 14 ng/l of high sensitivity cardiac
troponin.


Dr Carolyn
Lam:               
Right. Wow. What a great study. So systematic. So, all patients,
basically had readings before and after surgery. You know, I've
got so many questions, but I really, since you mentioned
Torbjorn, I would really like to ask his perspective on what you
think was the most striking parts of it and any questions you may
have on Christian.


Dr Torbjorn Omland:      First, I would
like to say that this is a very impressive study with some very
important results in a neglected area of medicine, really. So,
there are several very strong points with this study, and I think
that if we're able to, in such a large population, both have
pre-operative and post-operative and was able to calculate the
delta, and the importance of that was a very strong part of the
study, because it showed that, as Christian alluded to, the
baseline level did carry some information but there was also
important additional information from the serial measurements.
So, that's maybe one of the most important findings, I think.


                                               
Then, we addressed the question, how should we use these data?
So, my question to Christian is actually, how will screening for
exceptional myocardial injury affect clinical practice? Will it
lead to clinical deficiency interventions that will improve
outcome or will it just result in unnecessary testing?


Dr Christian Mueller:      Very good
important point, Torbjorn. I think you are absolutely right in
indicating that I think we are just beginning to understand all
of the part of physiology behind the event that we can now
capture, detect really, rather simple and precisely with troponin
screening. So, I think it's important that we highlight that the
part of physiology behind this event differs from patient to
patient. So, there are some patients who clearly have a type 1
myocardial infarction as the cause of myocardial injury. Very
likely, they are the minority in this setting. Likely, the
majority to have a kind of a type 2 myocardial infarction have a
physiology with imbalance between supply and demand, and again,
in these patients, of course, the management needs to be to
identify the trigger and to correct the trigger as rapidly as
possible. And it can be that detecting myocardial injury by the
rise in troponin, is the first indication that there is a problem
ongoing. Now the patient can have a physiological rearrangement
might have already been aware to the physicians if it's a type 1
myocardial infarction, then obviously very likely the same
therapy will be beneficial to this patient as we would apply in
spontaneous myocardial infarction.


                                               
A very important, and I'm glad you alluded to that the different
ways of, a rather wide variety of patient settings that are
summarized of the term perioperative myocardial injury. And the
consequences, likely will have to be individualized to really
ensure that we do something good for the patient.


                                               
And if I may, I would like to ask you and Carolyn for your
thoughts about the most appropriate wording. So, the current
wording that we used, of course, has to be in any scientific
precaution, a very conservative one, perioperative myocardial
injury. And it's important that, in fact, there are some entities
where likely injury is derived from the patients who have the
injury related to serious sepsis or related to a stroke, or
pulmonary embolism. However, it's very likely that the vast
majority of patients, the term perioperative myocardial
infarction would be appropriate. And, I think it's so important
to be aware of the implication that this, perhaps, on first
slight small difference might have. As long as we keep using the
term "injury", cardiologists will not really feel the same need
to be involved, the same need to really take care of this patient
as compared to the use of "myocardial infarction". So, I think
it's a balance between scientific accuracy, but also the need to
create awareness.


                                               
So, I feel that if cautiously applied, we'll do more good if
would more liberally use "myocardial infarction" within this
context. So, would you agree with this perchance?


Dr Carolyn
Lam:               
I think "injury" is at least better than what we used to say, "a
leak'. You know, we used to say, "Oh, it's just a troponin leak".
So, at least we're saying injury, recognizing that there is
damage done. I just wanna highlight that in your paper, something
that really struck me was that these patients with perioperative
myocardial injury or infarction, indeed did as badly as those who
did or did not fulfill myocardial infarction criteria. So, that
kind of supports what you are suggesting. I did get that right,
right? In your paper?


Dr Christian Mueller:      Absolutely. I
think for spontaneous myocardial infarctions, so clearly that the
criteria defined in the universal definition are mandatory.
There's nothing to discuss about, but we cannot criticize a
patient who is undergoing general anesthesia that he doesn't feel
chest pain, and therefore, we deny him the appropriate word of
the events. I think is just important that we clearly highlight
that it really can be the same event in the chest without
symptoms. But, not due to anything else but because he is
undergoing anesthesia.


Dr Carolyn
Lam:               
Very good point. You know, I would really like, though, to go
back to Torbjorn’s point, because I think that skeptics are gonna
say we've created a problem that we don't know how to solve, or
that we don't know how to treat. Do you know what I mean? So
we're detecting all these things, because now we have all these
assays. Patients are asymptomatic, and then we really don't know
whether it's modifiable. We don't know what to do to improve
outcome. So, could I ask both your expert thoughts on what the
future should hold? What is next step? Because, I see a gap.


Dr Torbjorn Omland:      Yes, that's of
course, a key question. So, I think we need to be innovative and
patient, because what we really need is clinical trials, perhaps
and more clinical trials looking into different strategies. But,
of course, that's also challenging because as Christian told us,
the path of physiology among this group of patients with
perioperative myocardial injury differs. So, what's going to be
appropriate for one patient, may not be the appropriate therapy
for the next patient. So, I think his suggestion of an
individualized approach is the best thing we can say at this
moment, while we are awaiting data from future clinical trials.


Dr Christian Mueller:      I fully agree
with Torbjorn [inaudible 00:19:53] what you said, you will
criticize some people will argue to that it's irrelevant. Why do
you measure this and you don't want to hear it? You don't want to
see it. But, I think it's important to remember the starting
point for us as cardiologists is to get involved is death. If
death is within 30 days after non-cardiac surgery in a patient
who was fit, relatively fit otherwise, who underwent a surgery
that was not a very high risk surgery from which he would expect
a certain percentage of patients to die. So, that's the starting
point. Again, of course perioperative myocardial infarction is
not the only contributor to perioperative death. But, it seems,
in addition to severe sepsis, to be the second commonest and most
important. So, I think it's really, really important to first, as
a really as a first important thing to increase the awareness of
this problem and to encourage our colleagues to start bringing
their research efforts, so that we get smarter in identifying the
underlying part of physiology in these infarcts or injuries.


                                               
Because, only once we understand, or have a reasonable
understanding what is the mechanism, we will be smart enough to
select the most important priority for any intervention study.


Dr Carolyn
Lam:               
Wow. What a wonderful note to end this podcast on. Words of
wisdom, as always from both of you, Christian and Torjorn.


                                               
See, listeners. Didn't I tell you this was gonna be a great
podcast? Don't forget to tune in again next week.