Circulation April 24, 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. Our featured paper
today is so important for cardiac surgeons and their patients. It
answers a question of whether targeting a higher versus a lower
blood pressure during cardiopulmonary bypass helps to prevent
cerebral injury. Curious? Well, more soon right after these
summaries.


                                               
In the first original paper this week, MicroRNA-22 is shown to be
a novel mediator of vascular smooth muscle cell, phenotypic
modulation, and neointima formation. Co-first authors, Drs. Yang
and Chen, co-corresponding authors, Dr. Zhang from Zhejiang
University and Dr. Xiao from Queen Mary University of London and
their colleagues used wire injury mouse models to show that
MicroRNA-22 controls vascular smooth muscle cell phenotype and
injury-induced arterial remodeling by modulating multiple target
genes, including methyl-CpG-binding protein 2, histone
deacetylase 4, and ecotropic virus integration site 1 protein
homolog.


                                               
The authors observed that MicroRNA-22 expression was suppressed
in human femoral arteries with atherosclerotic plaques, and that
there was an inverse relationship between MicroRNA-22 and its
target genes in healthy and diseased arteries. Furthermore, local
delivery of MicroRNA-2 in the injured arteries prevented adverse
arterial remodeling, thus suggesting that site-specific delivery
of MicroRNA-22 mimics may be a potential therapy for in-stent
restenosis.


                                               
The next paper adds to our understanding of the pathobiology of
pulmonary hypertension related to left-sided heart failure and
importantly adds histomorphometric evidence from human lung
specimens at autopsy or surgery.


                                               
First author Dr. Fayyaz, corresponding author Dr. Redfield, and
colleagues from the Mayo Clinic studied patients with heart
failure with preserved or reduced ejection fraction and pulmonary
hypertension and compared these to normal controls, as well as
patients with primary pulmonary veno-occlusive disease.


                                               
They found that patients with heart failure and pulmonary
hypertension had global pulmonary vascular remodeling with
thickening of the media and intima in arteries and thickening of
the intima in veins and small pulmonary vessels compared to
normal control subjects.


                                               
This venous and small-vessel intimal thickening was more severe
than the arterial intimal thickening in heart failure with a
pattern that was similar to patients with pulmonary
veno-occlusive disease. In fact, the severity of pulmonary
hypertension correlated most strongly with venous and small
vessel remodeling rather than arterial remodeling.


                                               
These findings expand our understanding of the pathobiology of
pulmonary hypertension in heart failure. It also suggests that
pulmonary venous remodeling in heart failure may predispose to
worsening alveolar edema with pulmonary vasodilators as in
primary pulmonary veno-occlusive diseases.


                                               
Are there sex and race differences in the lifetime risk of HFpEF
versus HFrEF? First author Dr. Pandey, corresponding author Dr.
Berry from UT Southwestern Medical Center, and their colleagues
used participant level data from two large respective cohort
studies, the Cardiovascular Health Study, and the Multi-Ethnic
Study of Atherosclerosis to determine remaining lifetime risk
estimates for heart failure with preserved and reduced ejection
fraction at different index ages.


                                               
They found that compared to women, men have a higher lifetime
risk of HFrEF, heart failure reduced ejection fraction with a
similar lifetime risk of HFpEF, or heart failure preserved
ejection fraction. Compared with blacks, non-blacks have a
similar lifetime risk of developing HFrEF but a higher risk of
HFpEF.


                                               
Lifetime risks of HFpEF and HFrEF were similar and substantially
higher in those with versus without antecedent myocardial
infarction.


                                               
In summary, these findings provide novel insights on sex and race
differences in the lifetime risks of HFpEF and HFrEF, and may
help health policymakers in appropriate resource allocation for
targeting HFpEF and HFrEF specific preventive therapies at the
at-risk population.


                                               
What are evidence-based blood pressure targets during pediatric
cardiopulmonary resuscitation? Well, first and corresponding
author Dr. Berg from Children's Hospital of Philadelphia and his
colleagues studied a multi-center population of children with
invasive arterial blood pressure monitoring during in-hospital
ICU cardiac arrest, and the Collaborative Pediatric Critical Care
Research Network Intensive Care Units, between 2013 and 2016.


                                               
They found that a mean diastolic blood pressure greater or equal
to 25 millimeters of mercury during cardiopulmonary resuscitation
in infants, and greater or equal to 30 millimeters of mercury in
children 1 year old or greater, was associated with a 70% greater
likelihood of survival to hospital discharge, and a 60% higher
likelihood of survival with a favorable neurologic outcome.


                                               
On the other hand, survival rates were markedly lower with mean
diastolic pressures less than 20 in infants and less than 25 in
children 1 year or older. Thus, clinicians should consider
targeting diastolic blood pressure of 25 or greater in infants,
and 30 or greater in children 1 year old or older during
cardiopulmonary resuscitation when invasive arterial blood
pressure is monitored.


                                               
That wraps up our summaries for this week. Now for our featured
discussion.


                                               
Does a higher versus a lower blood pressure target during
cardiopulmonary bypass surgery reduce the risk of cerebral
injury? Well, the feature paper today provides some answers, and
we have the first and corresponding author, Dr. Anne Vedel from
University of Copenhagen with us today, as well as our associate
editor, Dr. Timothy Gardner, who's a cardiac surgeon from
University of Pennsylvania.


                                               
Thank you so much for being with us today and this was a terrific
trial, a very difficult trial to carry out. Could you please tell
us a bit more about it?


Dr Anne
Vedel:                
Cerebral injury is an important complication after cardiac
surgery with the use of cardiopulmonary bypass. Up to half of our
patients suffer these perioperative silent strokes. Therefore, in
Copenhagen we conducted a trial investigating the importance of
two distinct blood pressure levels during cardiopulmonary bypass.
Now, on this subject of optimal perfusion strategy during bypass,
there are many opinions, but also a stunning lack of convincing
evidence, for instance, when it comes to blood pressure
management.


                                               
Now, the question is whether normal physiological principles,
such as cerebral autoregulation therapy, whether they apply
during bypass, or if perfusion pressure indeed does play a less
important role when blood flow is mechanically provided in an
uncomplicated and sufficient way by the heart and lung machine.


                                               
So, in a patient on the assessor-blinded randomized trial, we
allocated patients to a higher or a lower MAP target, 70 to 80,
or 40 to 50 millimeters of mercury, respectively, by titrating
intravenous norepinephrine during bypass.


                                               
Pump flow levels were set at 2.4 liters per minute per square
meter of body surface, and our primary outcome was the total
volume of new ischemic cerebral lesions, expressed as a baseline
MRI, and opposed to the difference between the baseline MRI and
the postop MRI on day three to six. Secondary outcomes were a
number of new ischemic lesions and newer psychological test
evaluations.


                                               
Now among the 197 patients enrolled who were scheduled for
coronary artery bypass, or heart valve repair surgery, or a
combination of both, we found that 53% of patients in the low
target group as opposed to 56 in the high target group had new
cerebral lesions on their postop cerebral MRI.


                                               
The primary outcome of volume of new cerebral lesions was
comparable between groups, and so was the total number of newer
lesions. No significant difference was observed in stroke rates
in frequencies of postoperative cognitive dysfunction, or in
severe adverse event rate.


                                               
Therefore, we concluded that among patients undergoing on-pump
cardiac surgery, targeting higher versus a lower mean arterial
pressure did not seem to affect the volume or number of new
infarcts.


Dr Carolyn
Lam:               
Wow, thank you so much, Anne. Tim, you think about these issues a
lot more than I do as a non-surgeon. Could you tell me what your
insights were?


Dr Tim
Gardner:               
You know, it's a very difficult study to do a randomized control
trial in this environment, and they're really to be congratulated
for doing it. As Anne acknowledges, this is not an area where
randomized trials are very frequent.


                                               
The first thing about the trial, I think, is a growing awareness
among all of us that there seems to be a lot of imaging evidence
of what we call injury or changes based on diffusion-weighted
imaging in patients after cardiopulmonary bypass. This is not the
first study that shows that.


                                               
But the question is are these incidental, trivial lesions? I'd
have to, again, ask Anne to clarify how many of the patients in
either group, what percentage had what we would consider evidence
of overt strokes?


Dr Anne
Vedel:                
Well, overt strokes, as opposed to silent strokes, 1 patient in
the lower target group had stroke and 6 patients in the high
target group, which corresponds to 1 as opposed to 7%.


Dr Tim
Gardner:               
That was not quite statistically significant difference but
headed in that direction with the assumption that if you have a
larger sample size there might be, in fact, some association with
overt stroke using the high target vasopressor approach, is that
right?


Dr Anne
Vedel:                
We can only speculate. But as you do, yes, I agree.


Dr Tim
Gardner:               
To go back to the original question, the significance of these,
well, you were referring to as silent strokes. Can you comment on
the clinical significance there? We hear of silent heart attack.
What is a silent stroke and what are the implications of that
long term for patients?


Dr Anne
Vedel:                
In other fields of research on the silent strokes, it's been
shown that they correlate to both frequency of postoperative
cognitive dysfunction and also later development of mild
cognitive impairment and dementia. But these kinds of results,
there isn't enough research in the field of cardiac study for us
to say the same. But those are the implications from other
research fields.


Dr Tim
Gardner:               
But you can understand from the perspective of a cardiac surgeon,
and this concern has been expressed and talked about in the
literature for 20 years or more, the possibility that even what
seems to be, with no injury apparent and no overt stroke, there
may be some neurological consequence to cardiopulmonary bypass.


                                               
So just to move on from that because I agree that we just don't
have any reliable information that these silent strokes result in
late or permanent injury, I think again the finding that
manipulating the blood pressure, which seems to be intuitively
beneficial in patients, especially elder patients, did not, in
fact, show any benefit and, in fact, may have been associated
with a slight increase in overt stroke. Is that a fair conclusion
from your study? A summary of your study?


Dr Anne
Vedel:                
I would say it is a fair conclusion, and surprisingly so. The
question is whether it is the blood pressure or the means that we
apply to have this increase in blood pressure that is the point
of interest here.


Dr Tim
Gardner:               
You mean whether, in fact, using the norepinephrine, the
vasoconstrictor, to increase the blood pressure whether that
itself, it certainly didn't benefit, it may have been a problem.


Dr Anne
Vedel:                
Exactly. That's what I speculate might be the case. But I also
think it's fair to say at this point that this is somewhat
artificial physiological scenario, the cardiopulmonary bypass.


Dr Tim
Gardner:               
I agree with that, that you're controlling blood flow and the
patient is exposed to a lower hemoglobin and oxygen-carrying
capacity and so on. But I think what struck me about your
findings, or strikes me about your findings, is what appears to
be in many of the patients, the low target patients, pretty
effective autoregulation of the cerebral circulation, despite the
artificiality of cardiopulmonary bypass.


                                               
I think that's, again, something that has been not well known or
well accepted by many people, thinking that if you lower body
temperature, you lower hemoglobin, autoregulation may not be
enough to maintain good cerebral perfusion. It looks like this
study shows that in these patients, autoregulation worked fine.
Is that fair?


Dr Anne
Vedel:                
Yes. Or sufficient blood flow was delivered. All in all, what's
new in our study, I think, is that hypertension per se shouldn't
necessarily be considered a proxy for hyperperfusion during
bypass.


Dr Tim
Gardner:               
Yeah, that's a very good qualification. So none of your patients,
despite being in their mid to late 60s had evidence of carotid
artery disease or whatever? Those patients were excluded from the
trial, is that right?


Dr Anne
Vedel:                
No, that's not correct. We didn't screen for carotid artery
disease because we don't routinely do that in our institution. As
we describe in our discussion, we included quite a heterogeneous
study sample by enrolling the patients that came to us. We didn't
screen and we didn't exclude these patients that you mention.


Dr Tim
Gardner:               
Do you know how does your group handle a patient that is known to
have carotid artery disease, comes in with a known either prior
endarterectomy or established disease? Do those patients, are
they treated any differently either as a result of the study or
just in general?


                                               
Because that is a targeted group of patients, at least in my own
experience, that we would be more concerned about allowing
autoregulation to be the determinant, feeling that if there is a
fixed stenosis in the carotid artery that we might need to
increase the mean arterial pressure.


Dr Anne
Vedel:                
I can certainly understand your point and, of course, it is a
concern in our center, as well. But having said that, there were
no patients in the PPCI trial that came to us with a history of
carotid artery disease, so it wasn't a concern for us in this
study.


Dr Tim
Gardner:               
That would be one point that I would make that we probably should
pay attention to patients who do come for surgery and have known
significant obstructive extracranial disease, but I understand
that you didn't specifically have those patients or were aware of
those patients.


                                               
I think that this is a very useful study for us concerned about
the possibility of inducing cerebral injury with cardiopulmonary
bypass. To some people it's sort of counterintuitive that
increasing perfusion pressure didn't improve the tolerance of
patients to cardiopulmonary bypass but that's why you did the
study. I think it's a very notable and important report that's
going to be in circulation.


                                               
The significance of these "silent infarcts" is merely something
that we have to sort of sort out. I know you said that silent
infarcts, as I agree, are associated with or presumed to be
predictive of later cognitive dysfunction, dementia and so on. It
really is a concerning message if that's the main message that
comes out of these imaging studies. Because these are patients
that, obviously, didn't have heart surgery for no reason, there
was obviously a compelling indication for patients to have it.


                                               
You would hate to re-ignite this concern as we had in and around
year 2000 when the group at Duke was talking about writing about
patients who had cognitive decline after cardiac surgery, were
going to end up being demented five or 10 years down the line,
so, that's from the perspective of a cardiac surgeon. Let's stick
with the evidence but let's follow-up and see how predictive
these silent infarcts are and what the consequences are long
term. Do you think that's fair, Anne? Am I making a fair
statement?


Dr Anne
Vedel:                
I absolutely do think it's fair. And for a cardiac surgeon as
yourself, I would find it very interesting to see that these kind
of studies are also conducted in TAVR patients where you have
sometimes a 200% incidence of these silent strokes.


                                               
I mean you have a good taste as a cardiac surgeon if you only see
them in 50% of your patients, understand me correctly, but I
don't necessarily think that this high incidence, it's high, yes,
but compared to other patient groups, such as TAVR patients, it's
not necessarily that bad.


Dr Tim
Gardner:               
Right. Anne, I don't know whether you've seen the editorial
that's going to accompany your paper, but it's very good. It's
very supportive of your study and has some good comments. You'll
be pleased with the editorial, I believe, if you haven't seen it.


Dr Anne
Vedel:                
Thank you very much. I'm happy to hear that. I know we do things
a bit controversially over here in Copenhagen, compared to many
centers in the U.S.


Dr Tim
Gardner:               
That is not what the editorialists think. An anesthesiologist
from Stanford and a neurologist from Penn, they have a very good
commentary on your study and the whole field, so you'll be
pleased.


Anne
Vedel:                      
I'm very happy to hear that. Thank you.


Carolyn Lam:      Well, listeners, I'm
sure you learned a lot. Thank you for joining us today, and don't
forget to tune in again next week.