Circulation December 12, 2017

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. Our feature discussion
today centers on patients with acute stroke due to large vessel
occlusion, and asks the question, "Does interhospital transfer
prior to thrombectomy relate to delayed treatment and worse
outcomes?" Well, stay tuned for more right after these summaries.


                                               
Our first original paper this week tells us that cardio
protection is alive, and mitochondrial cardiomyocyte
calcium-activated potassium channels of the BK type may be a
promising target. In this study from first author Dr.
Frankenreiter, corresponding author Dr. Lukowski, from University
of Tuebingen in Germany, the authors used a combination of
transgenic, pharmacologic and electrophysiological approaches to
show that mice with a cardiomyocyte-specific knockout of BK
channels had larger infarct size after 30 minutes of coronary
occlusion, and 120 minutes of reperfusion, and were less
protected by ischemic pre- and post-conditioning maneuvers, such
as guanylate cyclase stimulators or activators and
phosphodiesterase-5 inhibitors.


                                               
In a chronic infarct model, mice with cardiomyocyte-specific
knockout of BK channels had more fibrosis and lower left
ventricular function. Mechanistically, the activation of BK
channels in the inner mitochondrial membrane by cyclic GMP and
protein kinase G was identified by patch clamping, and resulted
in reduced formation of reactive oxygen species and activation of
cardioprotective signaling. In summary, deficiency of BK channels
in cardiomyocyte mitochondria rendered the heart highly
vulnerable to ischemic and reperfusion injury, whereas the
beneficial effects of cardioprotective agents known to target the
nitric oxide cyclic GMP pathway required these cardiomyocyte BK
channels. This thus establishes these cardiomyocyte mitochondrial
BK channels as a promising target for limiting acute cardiac
damage and adverse long-term events following myocardial
infarction.


                                               
The next study suggests that integration of maximal myocardial
blood flow and coronary flow reserve, termed coronary flow
capacity, may be helpful in predicting cardiovascular mortality
in patients with stable coronary artery disease. First author Dr.
Gupta, corresponding author Dr. Di Carli, and colleagues from
Brigham and Women's Hospital, quantify myocardial blood flow and
coronary flow reserve in more than 4,000 consecutive patients
referred for myocardial perfusion PET scans from 2006 to 2013.


                                               
Maximal myocardial blood flow of less than 1.8 mLs per gram per
minute, and coronary flow reserve of less than two, were
considered impaired. Four patient groups were then identified
based on the concordant or discordant impairment of maximal
myocardial blood flow, or its coronary flow reserve. The authors
found that in patients with known or suspected coronary artery
disease, impaired coronary flow reserve with preserved maximal
myocardial blood flow identifies patients at an increased risk of
cardiovascular mortality, despite a lack of myocardial ischemia.
Patients who may be targeted for initiation or intensification of
lifestyle preventive therapies for cardiovascular risk reduction.
Conversely, preserved coronary flow reserve, even in the absence
of impaired myocardial blood flow, identifies patients at low
risk, in whom the need for revascularization should be
reevaluated.


                                               
The next study provides insights into cardiac regeneration,
particularly with regards to using resident cardiac progenitor
cells expressing the tyrosine kinase receptor c-Kit, which is
being tested in clinical trials. In this study from first authors
Dr. Chen and Zhu, corresponding authors Dr. van Berlo from
University of Minnesota and colleagues, the authors used
single-cell sequencing and genetic lineage tracing to show that
there was innate heterogeneity within these c-Kit positive
cardiac cells, where some have either endothelial or mesenchymal
identity. Cardiac pressure overload resulted in a modest increase
in c-Kit derived cardiomyocytes, with significant increases in
the number of endothelial cells and fibroblasts. On the other
hand, doxorubicin-induced acute cardio toxicity did not increase
c-Kit derived endothelial cell fates, but instead induced
cardiomyocyte differentiation.


                                               
Although the overall rate of cardiomyocyte formation from c-Kit
positive cells was below clinically-relevant levels, the authors
further showed an important role for p53 in the differentiation
of c-Kit positive cells to cardiomyocytes. Thus, this paper shows
that different pathologic stimuli induced different cell fates in
c-Kit positive target cells. These are novel findings that could
aid in the development of strategies to preferentially regenerate
cardiomyocytes.


                                               
Since December 2014, a series of pivotal trials have shown that
endovascular thrombectomy was highly effective in acute stroke
management, prompting calls for reorganization of stroke systems
of care. But how have these trials influenced the frequency of
endovascular thrombectomy in clinical practice? Well, the last
original paper in this week's journal tells us how. First and
corresponding author, Dr. Smith from University of Calgary in
Alberta, Canada, and colleagues, used data from the Get With The
Guidelines stroke program to determine how the frequency of
endovascular thrombectomy has changed in U.S. practice. They
analyzed prospectively-collected data from a cohort of more than
two million ischemic stroke patients, admitted to more than 2,000
participating hospitals between 2003 and the third quarter of
2016.


                                               
The authors found that the use of endovascular thrombectomy for
acute ischemic stroke accelerated sharply after the publication
of pivotal randomized control trials beginning in December 2014.
The endovascular thrombectomy case volume doubled at hospitals
providing therapy. In the third quarter of 2016, endovascular
thrombectomy was provided to 3.3% of all ischemic stroke
patients. This represented 15.1% of all patients who were
potentially eligible for endovascular thrombectomy based on
stroke duration and severity. In summary, endovascular
thrombectomy use is increasing rapidly, however there are still
opportunities to treat more patients. Reorganizing stroke systems
to route patients to adequately resourced endovascular
thrombectomy-capable hospitals might increase treatment of
eligible patients, improve outcomes, and reduce disparities.


                                               
Coming right up, we will be discussing even more about
endovascular thrombectomy in acute stroke management. Just hang
on, our feature discussion is coming right up.


                                               
Endovascular treatment with mechanical thrombectomy is beneficial
for acute stroke patients suffering a large vessel occlusion. And
that is in the guidelines, however we also know that treatment
efficacy is highly time-dependent. And so, will interhospital
transfer to an endovascular-capable center help in cases of acute
large vessel stroke? Well, today's feature paper really helps to
present novel data to answer that question. And it is from the
STRATIS study. I'm so delighted to have with us the first and
corresponding author, Dr. Michael Froehler from Vanderbilt
University Medical Center, who will tell us about his findings,
as well as Dr. Graeme Hankey, associate editor from University of
Western Australia, joining us today. Welcome, gentlemen.


Dr. Michael Froehler:     Hello Carolyn.


Dr. Graeme Hankey:       Thank you
Carolyn.


Dr. Carolyn
Lam:              
Thanks for making the time. Mike, tell us about the STRATIS
study. What inspired it, what you found.


Dr. Michael Froehler:     Well, the STRATIS
study was actually a large registry of the use of the Solitaire
device for large vessel occlusion. Those results, the primary
results, were published separately. But what we did in this study
is look at one key aspect of the system of care for stroke
delivery, in terms of its effect on time to treatment and patient
outcomes.


                                               
And so in short, what we found is that patients that are
transferred from one hospital to another for mechanical
thrombectomy take longer to receive treatment, and do worse in
terms of functional outcome, compared to the patients that
present directly to that thrombectomy center.


Dr. Carolyn
Lam:              
Wow. Could you put some numbers to that?


Dr. Michael Froehler:     Well, so we looked
at 984 patients, almost a thousand patients. And what we found
was that the time from stroke onset to revascularization, until
the time the vessel was actually opened, was 202 minutes on
average, for patients that presented directly to the thrombectomy
center. Compared to over 311 minutes for patients that were
transferred from one hospital to another. So that's a difference,
on average, of over 100 minutes.


Dr. Carolyn
Lam:              
And I really was impressed with this other analysis you did. So I
was wondering if you could share, where you did a hypothetical
bypass modeling. Could you tell us about that? Because I thought
that was really practical with a feasible message as well.


Dr. Michael Froehler:     I'm excited about
that, and I should also share with you that we're working on a
more in-depth bypass analysis, to really understand the
implications of going to one center directly versus another. But
the model that is built in to this publication is really designed
to answer one or two questions. And the first is, how much time
would we save if we went directly to the thrombectomy-capable
center, compared to what actually happened? Meaning the patient
was taken to a regional hospital and then subsequently
transferred to the thrombectomy-capable center. And this was
basically an ideal scenario.


                                               
So if they were taken to one hospital and then transferred to
another, we simply calculated what the maximum driving time from
the starting position to the thrombectomy-capable center would
be. And that did rest on the assumption that you actually had to
drive past the first hospital. We didn't take any shortcuts in
terms of the driving, and probably that small amount of driving
time is actually shorter than the number that we found in our
calculation.


                                               
So the first question was, how much time would we save with that
bypass? And the second question was, what kind of impact would
that have on IV-tPA? Because, as a lot of us are thinking right
now, with strong evidence in support of endovascular therapy for
large vessel occlusion, if necessary how should we prioritize
getting to endovascular treatment versus the standard therapy
that we've known for 20 years, which is IV-tPA? And if you've got
a choice, which one is more important?


                                               
I don't know the answer to that question, but to try and help
lead up to it, we did this hypothetical bypass analysis to look
at the impact of bypass, driving directly to the thrombectomy
center, the impact of that on the time to delivery of IV-tPA. And
so that was really the second question that we asked with this
hypothetical bypass analysis.


Dr. Carolyn
Lam:              
Yeah. I love that analysis, because I agree with you, it's a
very, very practical question, and it's the way we clinicians
think, right? So, tell us, what's the bottom line?


Dr. Michael Froehler:     So, the bottom line
is, you're gonna save about an hour and a half if you bypass the
regional hospital and go directly to the thrombectomy-capable
center. On average, you're gonna get to the ultimate treatment
center 91 minutes sooner, compared to the transferred group.
Contrast that 91-minute time savings with a delay of IV-tPA
delivery of 12 minutes. So yes, tPA will be delivered a little
bit later, but endovascular therapy will be delivered much
sooner.


                                               
Now, that solution is probably not going to work everywhere,
depending on your geography. So one of the other things we did
within the hypothetical bypass analysis was limit that analysis
only to patients who were transferred within a 20-mile radius.
And that doesn't seem like a long distance, but actually there's
a lot of patients in that group, that are still taken to the
nearest hospital and then need to be transferred to another
hospital that may be less than 20 miles away.


                                               
So if we looked at that group of patients, then thrombectomy is
still performed an hour and a half earlier, in that analysis it
was 94 minutes earlier, but IV-tPA was delayed by only seven
minutes. So certainly, there is a large group of patients out
there that are perhaps being taken to hospitals that are not
necessary, it's not a necessary stop.


Dr. Carolyn
Lam:              
Wow, Mike, this is really amazing results, it's starting to make
me think of the old days of acute myocardial infarction
treatment, when we were thinking of intravenous thrombolytics,
comparison to primary PCI, an analogy and comparison that was
also mentioned in the accompanying editorial that you invited.
Graeme, would you like to share some of your thoughts on the
implication of all this?


Dr. Graeme Hankey:       Just to
take a step back, of course this begins with a stroke occurring
out in the field. And unlike acute coronary syndromes, where
chest pain is the major symptom, there are many symptoms of
stroke. And the first problem is trying to identify the patient
who has actually had a stroke, and in particular, one of the 15%
or so who's had a large vessel occlusion, who's amenable to large
vessel mechanical thrombectomy. So in the field we have an issue
with clinical triage, and trying to work out who's the one in six
who really need endovascular therapy, and who are the five in six
who perhaps don't.


                                               
And we're trying to develop clinical triage scales like the RACE
scale to work out in the ambulance where someone should go. But
we still haven't nailed that yet. Then you have scales that are
very sensitive but not very specific, and have a high sort of
false-positive rate. So then the question at the ambulance is,
where does it go, to the hospital, the primary stroke center
nearby, and give the patient the earliest opportunity to get tPA?


                                               
And that's the potential benefit of early transfer to a primary
center, but tPA is not very effective in dissolving these big
clots in large arteries. And so, of course the trials have shown
a substantial benefit of endovascular therapy to remove the clots
via thrombectomy. But those resources, they're only really
limited to comprehensive stroke units, and that's what this paper
was about. So the trade-off is early transfer to the primary
center so you can get some tPA, versus delaying, as Michael has
shown, by 1 1/2 to two hours on average, to get to a
comprehensive center that can access the expertise of
endovascular thrombectomy experts.


                                               
And this paper is really taking us forward in emphasizing again
that time is brain, and we really don't want to delay. Perhaps
there's a small trade-off in driving a little bit further,
another 20 miles at the most perhaps, to get to a comprehensive
center directly. And there may be some who are not shown to have
a large vessel occlusion at that comprehensive stroke center, but
the overall benefit is probably offset, the few who might miss
out on tPA. And so this is a really important study, the largest
registry of large vessel occlusion patients to observe and
compare the outcomes after adjusting for all the different
factors. And give us some clues, that perhaps we really need to
be trying to focus on building our resources in comprehensive
stroke centers, and also being able to more accurately identify
those who are likely to benefit and go directly there.


Dr. Michael Froehler:     I agree with
everything Graeme said, and I would just amplify one thing that
he said, that it does depend on distance, and those distances in
turn depend on your own geography. We did an analysis of all our
transferred patients and then limited it to those that were
within a 20-mile radius. For Graeme in Western Australia, you
know Graeme's mailbox is probably 20 miles away. And so there are
huge distances in Western Australia to account for. And it may
not be possible.


Dr. Carolyn
Lam:              
Contrast that to me in Singapore. I think if I drive any bit
more, and I'll be driving out of my country already.


Dr. Michael Froehler:     I think that you
make a great point though, Carolyn, that the solution that works
for metro Singapore is not what's going to work for rural Western
Australia. And we've seen this in New York City, for example. My
colleagues at Mount Sinai are looking at different ways to
deliver care across metro New York, which obviously is very
different compared to myself in Nashville, Tennessee. So the
right solution is not gonna be the same solution for everyone.


Dr. Graeme Hankey:       And that's
right Carolyn, because in rural places like out in Western
Australia, we are learning now that another important message is
to try and help upscale and reorganize our primary stroke
centers, or just our medical centers out in the rural and remote
areas. Because as Mike's paper shows, the delays once someone
comes to a primary stroke center or a rural center, is about 30
minutes for diagnosis, about 30 minutes to arrange the transport,
and about 30 minutes to actually do the transport.


                                               
So we need to once trying to develop comprehensive stroke units,
also build up those peripheral hub and spoke centers to be more
slick with their diagnosis, arrangement of transport, and
transport times. And one of the important things I think is, we
need our primary centers, when a stroke does come, to not just do
a plain CT to exclude hemorrhage, but to do a CT angiogram at the
time. And find out those who really do have an occlusion, rather
than putting them all on the plane and sending them down, and
quite a few of them don't actually have an occlusion by the time
that they've got here. They haven't been fully investigated, it's
just an extra five minutes to do the contrast CT angiogram at the
time in the primary center if they're gonna go there.


Dr. Michael Froehler:     I think the one
other thing I should add, and this is just to reflect back on
something Graeme said a minute ago, is that one of the
differences we found that really came out of that bypass analysis
is the impact on tPA was smaller than we expected. Because the
door-to-needle times are actually much longer at the regional
hospitals that are not thrombectomy-capable, compared to the
thrombectomy centers themselves, that are not only obviously
delivering mechanical thrombectomy, but are actually delivering
IV-tPA much sooner in terms of door-to-needle times.


Dr. Carolyn
Lam:              
So, room for improvement even for non-endovascular-capable
centers, isn't it?


Dr. Michael Froehler:     Right, I think it's
another area where there's room for improvement.


Dr. Carolyn
Lam:              
Please don't forget to tune in again next week.