Circulation July 17, 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.


                                               
In this day and age of endovascular treatment for acute ischemic
stroke, does time to treatment really matter? Well, we will be
discussing results of the MR CLEAN Registry from real-world
clinical practice, coming right up after these summaries.


                                               
The first original paper this week describes the first mouse
model of progerin-induced atherosclerosis acceleration. Progerin
is an aberrant protein that accumulates with age, causes a rare
genetic disease known as Hutchinson-Gilford Progeria Syndrome.
Patients with Progeria Syndrome have ubiquitous progerin
expression and exhibit accelerated aging and atherosclerosis,
dying in their early teens mainly from myocardial infarction or
stroke. The mechanisms underlying progerin-induced
atherosclerosis remain unexplored, in part due to the lack of
appropriate animal models. First author Dr Hamczyk, corresponding
author Dr Andrews, and colleagues from CNIC in Madrid performed
an elegant series of experiments and generated not only the first
mouse model of progerin-induced acceleration of atherosclerosis,
but also provided the first direct evidence that progerin
expression restricted to vascular smooth muscle cells but not to
macrophages was sufficient to induce premature atherosclerosis
and death. Progerin-induced loss of vascular smooth muscle cells
caused atherosclerotic plaque destabilization that led to
myocardial infarction. Ubiquitous and vascular smooth muscle cell
specific progerin expression increased LDL retention in aortic
media, likely accelerating atherosclerosis.


                                               
The next original paper implicates dysregulation of mitochondrial
dynamics as a therapeutic target in human and experimental
pulmonary arterial hypertension. Now, mitotic fission is
increased in pulmonary arterial hypertension. The fission
mediator, dynamin-related protein 1, or Drp1, must complex with
adaptor proteins to cause fission. In the current paper from
co-first authors Dr Chen and Dasgupta, corresponding author Dr
Archer from Queens University in Ontario Canada, and colleagues,
the authors examined the role of two recently discovered but
poorly understood Drp1 adaptor proteins known as mitochondrial
dynamics protein of 49 and 51 kilodalton. They found pathological
elevation of these mitochondrial dynamic proteins in pulmonary
artery smooth muscle cells and endothelial cells in both human
and experimental pulmonary arterial hypertension that accelerated
mitotic fission and supported rapid cell proliferation.
Mitochondrial dynamics protein's expression was epigenetically
upregulated by a decreased expression of microRNA-34a-3p.
Circulatory microRNA-34a-3p expression was decreased in both
patients with pulmonary arterial hypertension and preclinical
models, silencing the mitochondrial dynamics proteins or
augmenting microRNA-34a-3p regressed experimental pulmonary
arterial hypertension, thus, proving to be potential new
therapeutic targets for pulmonary arterial hypertension.


                                               
Dyslipidemia guidelines currently recommend that non-HDL
cholesterol and apolipoprotein B, or apoB, are secondary targets
to the primary target of LDL cholesterol. However, how frequently
does non-HDL cholesterol guideline targets change management, and
what is the utility of apoB targets after meeting LDL and non-HDL
targets?


                                               
Well, answers are provided in the next paper from first author Dr
Sathiyakumar, corresponding author Dr Martin, and colleagues from
Johns Hopkins University School of Medicine. These authors
analyzed more than 2,500 adults in the US National Health and
Nutrition Examination Survey, as well as more than 126,000
patients from the Very Large Database of Lipids Study with apoB.
They identified all individuals as well as those with high-risk
clinical features, including coronary disease, diabetes, and
metabolic syndrome who met the very high and high-risk guidelines
targets of LDL cholesterol of less than 70 and less than 100
mg/dL, respectively, and this was measured using either the
Friedewald estimation or a novel, more accurate method. They
found that after using the more accurate method of estimating LDL
cholesterol, guidelines suggested non-HDL targets could alter
management in only 1 to 2% of individuals, including those with
coronary disease and other high risk clinical features.


                                               
However, using the Friedewald estimated LDL cholesterol gave a
much higher percentage. Among all individuals with both LDL
cholesterol less than 100 and non-HDL cholesterol less than 130
mg/dL, only 0-0.4% had an apoB above or equal to 100 mg/dL. Thus,
the utility of current non-HDL targets appears to be contingent
on the accuracy of LDL cholesterol estimation. When using a
novel, more accurate estimation method to assess LDL cholesterol,
the non-HDL cholesterol is infrequently above current guidelines'
suggested targets after the LDL target is met. Current guidelines
suggest that apoB targets also provide only modest utility after
cholesterol targets are met. These findings were robust to
high-risk clinical features, sex, fasting status, and presence of
lipid-lowering therapies.


                                               
The final paper tells us that HIV infection increases the risk of
developing peripheral artery disease. Dr Beckman from Vanderbilt
University Medical Center and colleagues studied almost 92,000
participants in the Veterans Aging Cohort Study from 2003-2014
over a median follow-up of nine years. They excluded participants
with known prior peripheral artery disease or prevalent
cardiovascular disease. They found that infection with HIV was
associated with a 19% increased risk of incident peripheral
artery disease beyond that explained by traditional
atherosclerotic risk factors. Once peripheral artery disease had
developed, HIV infection increased the risk of mortality compared
to uninfected patients. Whereas for those with sustained CD4 cell
counts above 500, there was no excess risk of incident peripheral
artery disease events compared to uninfected people. Furthermore,
worsening HIV infection as measured by CD4 cell count and HIV
viral load was associated with increased incident peripheral
artery disease and mortality. In summary, HIV infection increased
the risk of developing peripheral artery disease and mortality.
The findings also suggest that aggressive antiretroviral therapy
to reduce viral load and increase CD4 cell counts may reduce the
risk of developing peripheral artery disease. Furthermore,
clinicians should solicit clinical complaints and physical signs
consistent with peripheral artery disease to facilitate the
diagnosis of peripheral artery disease in patients with HIV and
ensure the addition of guideline-based anti-atherosclerotic
therapies in these patients.


                                               
Well, that wraps it up for our summaries. Now for our feature
discussion.


                                               
When it comes to acute ischemic stroke treatment, we've learned
from trials of intravenous thrombolytics that time is brain. But
what about the situation with endovascular treatment of strokes?
Also, what's the situation like in the real world? Well, today's
featured paper really provides precious data telling us about
time-to-endovascular treatment and outcomes in acute ischemic
stroke. I am so delighted to have with us the first and
corresponding author of the MR CLEAN Registry, Dr Maxim Mulder
from Erasmus University Medical Center, as well as our
editorialist, Dr Micheal Hill, from University of Calgary, and
our associate editor, Dr Graeme Hankey, from University of
Western Australia, all here to discuss this hugely important
topic.


                                               
Maxim, could we start with you? So, MR CLEAN Registry means there
was a MR CLEAN trial. Could you tell us a little bit more about
your paper?


Dr Maxim
Mulder:          
Sure, well to start with, I think it's important to make sure all
the people know the difference between the MR CLEAN trial and the
registry since of course the trial was to show whether the
intra-arterial treatment is effective when it comes to acute
ischemic stroke treatments and then, of course, for people
treated within six hours. When the MR CLEAN trial finished we
continued in the Netherlands with all the participating centers
from the trial to gather all the data from everybody who is
treating in the whole country with the intra-arterial treatment,
but they're not anymore in the light of the trial but in the
clinical practice. We've had a lot of trials, but we don't have a
lot of clinical practice date yet of the intra-arterial
treatment, so that's where it all started.


                                               
So, what we found is we consider our data, so with the least
possible selections or the only selection was basically to treat
within six and a half hours and have patients that had a proven
large vessel occlusion that were treated in the Netherlands and
of course as we also know from when intravenous therapy was
introduced that what happens in clinical trials doesn't
necessarily happen when a new treatment is introduced into
clinical practice. There are less strict criteria for patients to
get treated, and you know everybody, of course, there is a lot of
debate about which patients should be treated. In clinical trials
it is very strictly coordinated, but in clinical practice there's
a lot more room to have an interpretation and also treat a
different population. So, we also see that our population is
somewhat older and has more comorbidities than in all the trials.
Also what we found, of course, our most important finding was
that when compared to all the trials or the large trials combined
together in the Emberson analysis about time that when we look at
the influence or the association of time with functional outcome
of intra-arterial treatment that this association is clearly
stronger than we found in the previous, the trial data.


                                               
So, I think that's a very important finding. Also, for everybody
who's now treating this patient in clinical practice.


Dr Carolyn
Lam:               
Exactly. I mean this is really stunning results. If I could
paraphrase from your paper, every hour delay in time from stroke
onset to the start of endovascular treatment resulted in a 5.3%
decreased probability of functional independence and a 2.2%
increase in mortality. This is stunning. Thank you, thank you for
publishing these results with us in Circulation. I would like to
ask Michael, I love the point you made in the editorial that time
of stroke onset is really quite a difficult thing to determine.
Could you tell us your thoughts about that, Michael?


Dr Micheal
Hill:                 
I mean, it's something like 15-20% of the time stroke is
unwitnessed, either because stroke occurs in sleep and the
patient is discovered with their stroke symptoms on awakening. Or
the patient is simply alone and has their stroke unwitnessed by
any bystander. Even in so-called witness stroke, there are
probably significant errors in determining the exact time of
stroke onset because it's an emergency, and everybody's flustered
and time anchors are not necessarily well known. And, so, I think
it's an important point that the actual measurement of time is
challenging, yet it's still an easier clinical tool for us to use
in gauging the extent or evolution of stroke. That's the most
important thing to point out here is that this population effect
that Max has observed in the MR CLEAN registry is certainly
concordant with clinical trial data.


                                               
I certainly think it's correct, and, as you pointed out in your
comments, dramatic, but a really important issue is that for the
individual patient, there's quite a lot of variance in the
evolution of stroke. So, whereas, on a population basis, it's
absolutely true that the average time from estimated time of
stroke onset to treatment initiation is absolutely critical; in
some patients, the individual might be still a good candidate for
treatment even in late time windows, and some patients, even
after a couple hours, the damage is already extensive, and they
may not be good candidates for treatment. It still requires
individual decision making, and it still leaves a lot of room for
clinical judgment largely based on imaging.


Dr Carolyn
Lam:               
True, and I think you've really succinctly put that solid
take-home message in the title really, which is acute ischemic
stroke biology really demands fast treatment. I think that's the
one thing that we'd really like clinicians to come away with. You
agree?


Dr Micheal
Hill:                 
Absolutely. Especially, I think, the advantage of looking at
whole populations and large, I mean this is a large registry, the
MR CLEAN registry, and the group should be congratulated because
it's clearly the biggest registry in the world right now of
available data, and it's only getting larger week by week as they
carry on with their work. You know the whole Netherlands group,
the MR CLEAN group, are a fantastic group, but absolutely right,
on a population basis, we absolutely have to get our systems in
place so that on average we're treating patients incredibly fast.
On an individual basis, the clinicians and the teams treating an
individual patient still need to make judgments about that
patient's eligibility for treatment. It's easy when the times are
fast, so if you're an hour and a half from onset, nearly
everybody's gonna be a good candidate for treatment, but as time
elapses you need to make judgements on the basis of imaging.


Dr Carolyn
Lam:               
Well put. You know, Graeme, you're over there in Australia. What
are your take-home messages about how generalizable these
findings are to places outside perhaps of the Netherlands?


Dr Graeme Hankey:        I
think you're asking about the external validity. I think the
internal validity is certainly there. As Michael said, this is
the largest registry that we have that's been published data on
this before. It's certainly novel, and we're very confident that
the results are valid, although this is an observational study
and not a randomized trial. The association between time and
outcome seems to be independent of the major patient factors that
may influence time to endovascular therapy. For example, younger
people who are less frail and they're alert and they're mobile
can get to treatment earlier. So, you might say, well of course
they're gonna have a better outcome. But these factors were
adjusted for. And, of course, there are procedural factors that
could influence the association between time and outcome, but
we're very confident in the results and the novelty of them in
supporting and building on the randomized trial data.


                                               
We're also very confident in the registry and the nature of the
population. The results are likely to be generalizable beyond the
Netherlands population where this was conducted in routine
clinical practice, certainly across Caucasian populations that
are similar and with similar stroke interventional and assessment
protocols, and I would hope to see this sort of study validated
externally in other populations. But, also, as Michael said, I
think this study not just highlights the importance of time as a
factor and its implications for systems of care and recognizing
people with disabling stroke and ensuring they’re assisted
urgently to the appropriate imaging but also to acknowledge that
time isn't the only factor. And as Michael has alluded to, our
brain tissue has different collateral circulations and different
probable genetic factors and metabolic factors. So, someone with
a stroke at one hour, it might be all over for them. Whereas,
another person with a stroke at 24 hours ago, they might have
salvageable tissue.


                                               
So, although, generally time is an important prognosticator as
we've learned here, there are probably other factors that need to
be considered and accounted for. But this certainly takes us a
step forward, and, in answer to your question, I think we have
confidence in its generalizability.


Dr Carolyn
Lam:               
Thank you Graeme. Maxim, in line with that, are there any next
steps you plan?


Dr Maxim
Mulder:          
In light of the most recent trials, the DAWN and DEFUSE 3 trial
about 6 to 25-hour, 24-hour window, I think that both of the
trials are very exciting, and they shine a new light into a new
set of patients that are still able to offer a great benefit
intra-arterial treatment. In my opinion, the most important
thing, especially in those two trials, those are highly selective
patients, especially selected on all the extra imaging
parameters, and I guess that there's a whole larger population
that could still benefit in this time window and that's also one
of the things we're currently studying in one of our new trials
in the Netherlands in the MR CLEAN-LATE trial, and that is
randomizing patients who are having a large vascular occlusion 6
to 24 hours, and the only extra criteria they should meet is they
should have at least a little bit of collateral circulation on
the ischemic brain side.


Dr Carolyn
Lam:               
Michael and Graeme, what do you think are the priorities for next
steps in research.


Dr Micheal
Hill:                 
I guess overall in the field, I don't think there's any doubt
that faster treatment is better. What we need to do across the
world is make sure that everybody's receiving it on a system-wide
basis. Right? I think there needs to be a lot of more careful
work done on getting systems of care in place to make sure that
patients are getting the treatment they can get. We have very
many weaknesses. Some are related to lack of accreditation. Some
are related to the resources required to get people treated
quickly. Some are related to continuing resistance in some
specialties to even giving intravenous thrombolytic drugs. So, I
think faster treatment in general for acute stroke is a theme;
it's not just limited to endovascular treatment. It's treatment
for patients for intravenous thrombolysis. It's also actually
true for TIA and minor stroke. We've had recent data on fast
antiplatelet therapy, so, it's not an emergency in the same way
in terms of minutes, but it's still a general theme of acute
stroke care.


                                               
We need to be like the Ferraris and the Formula One, right? And
get ourselves moving. That's a big challenge for people. Right?
It's a big stress on systems. But, I think there are other
examples in medicine. We've seen this evolution in acute coronary
care, and we've seen the evolution in acute trauma care. In many
ways, the next things that need to really continue to happen are
publications like this and getting the message out that people
need to start changing their mind. The biggest thing that I find
when I talk to people or talk at meetings or talk to
administrators is that they say, "Well, we can't do this many CTs
that fast. We can't respond that fast." And the answer is
actually that you can't change the biology of the disease, so if
you decide you wanna treat stroke patients, you better figure out
how to change your systems. It's a question of will here rather
than trying to bend the disease to the system.


Dr Carolyn
Lam:               
Wonderfully put. Can't change the biology so we better change the
systems. How about you, Graeme? Any last words?


Dr Graeme Hankey:        Just
to concur with Michael’s comments there and Max's underlying
theme that time is very important. And as Michael alludes to,
it's not just acute ischemic stroke due to large vascular
disease, it's also acute intracerebral hemorrhage. We're learning
now really if we're gonna have an effect in the bleeding brain
probably we have to do that within the first three hours and
maybe not be waiting so late. And as Michael alludes to, someone
with a minor ischemic stroke who's had a hot volcano gone off in
their neck, as you know, ruptured atherosclerotic plaque, it's
like those volcanoes in Hawaii, they're gonna keep going off
again. And the risk is 5% in the next two days and 10% in the
next week. So, a TIA and a mild ischemic stroke, it is a medical
emergency to find the cause and to get it treated, and that's why
the synopsis of this message from Max's study is that people, if
they do avail themselves of acute assessment early, even if they
don't have a large vessel occlusion causing an ischemic stroke,
they may actually have their intracerebral hemorrhage treated
quickly or, more evidence based at the moment, their TIA or mild
ischemic stroke have the cause ascertained and treated emergently
and reduce that early risk of recurrence should they survive.


Dr Carolyn
Lam:               
Excellent points. Thank you so much, gentlemen. This has been an
amazing podcast.


                                               
Thank you so much for joining us today. Don't forget to tune in
again next week, listeners.