Circulation March 26, 2019 Issue

Dr Carolyn
Lam:               
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
co-hosts, I'm Dr Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr Greg
Hundley:            
I'm Greg Hundley, associated editor from the Pauley Heart Center
at VCU Health Sciences in Richmond, Virginia.


Dr Carolyn
Lam:               
A big number of acute ischemic stroke patients receiving
endovascular therapy in the United States are receiving this
therapy only after inter-hospital transfer. What are the temporal
transient outcomes following this inter-hospital transfer? Very
important discussion coming right up with our featured paper. But
for now, sit back, relax with us. We're going to discuss a couple
of papers that we found were interesting in this week's journal.


Dr Greg
Hundley:            
Very good, so thanks Carolyn. I'll start off, and I'm going to
talk a little bit about stress induced cardiomyopathy, and we
also know it as takotsubo cardiomyopathy, looking at a paper from
Dana Dawson from the University of Aberdeen in the United
Kingdom. Takotsubo cardiomyopathy can result in a heart failure
phenotype with a prognosis comparable to myocardial infarction.


                                               
In this study, the investigators hypothesize that inflammation is
central to the pathophysiology in natural history of takotsubo
cardiomyopathy. They prospectively recruited 55 patients with
takotsubo cardiomyopathy, and 51 age, sex, and comorbidity match
control subjects.


                                               
During the index event, and at five months of follow-up, the
patients with takotsubo cardiomyopathy underwent a cardiac MRI
study in which they looked at ultra-small, super paramagnetic
particles of iron oxide, or USPIOs, enhancement for detection of
inflammatory macrophages in the myocardium. What would the
studies show? Patients with acute takotsubo cardiomyopathy had
macrophage-mediated myocardial inflammation.


                                               
They also demonstrated modulation of peripheral monocyte subsets
and increased systemic pro-inflammatory cytokines. This systemic
inflammation persisted for five months, and then at that
five-month time point, the cardiac MRI evidence of the macrophage
presence was diminished.


Dr Carolyn
Lam:               
Wow, Greg. So this is right up your wheelhouse, isn't it? Can you
explain? What are the clinical implications of these MRI
findings?


Dr Greg
Hundley:            
It was really interesting. For the first time, they've linked an
ongoing inflammatory process using the USPIO contrast agent with
MRI actually going on or operative in the heart, and they
associate that with systemic markers in the circulation.


                                               
They help us elucidate the mechanisms and the pathogenesis of
takotsubo cardiomyopathy, and systemic and myocardial
inflammation really may start to now serve as a therapeutic
target for patients with acute takotsubo cardiomyopathy.


Dr Carolyn
Lam:               
Very interesting. From stress-induced cardiomyopathy to early
onset myocardial infarction. The first paper I chose really
answers the question, "What is the relative prevalence and
clinical importance of monogenic mutations, that is, a single
mutation that significantly increases risk, versus a polygenic
score, which really measures the cumulative impact of many common
variants, in early onset myocardial infarction?"


                                               
The co-corresponding authors were Doctor Amit Khera and Sekar
Kathiresan and both from Massachusetts General Hospital, and they
performed deep coverage, whole genome sequencing of more than
2,000 patients from four racial subgroups hospitalized in the
United States with early onset myocardial infarction defined as
myocardial infarction before the age of 55 years, and compared
this to 3,761 population base controls.


                                               
What they found was that a monogenic mutation related to familial
hypercholesterolemia was identified in 1.7% of the patients, and
associated with a 3.8-fold increased odd of myocardial
infarction. In comparison, the high polygenic score, which was
composed of 6.6 million common DNA variants and defined as the
top 5% of the control population distribution, now, that was
identified in 10 times as many patients, so 17% of patients, and
associated with a similar 3.7-fold increased odds of myocardial
infarction.


Dr Greg
Hundley:            
Interesting. How do we apply this clinically, Carolyn?


Dr Carolyn
Lam:               
These findings really lay the scientific foundation for the
systematic identification of individuals born with a
substantially increased risk of myocardial infarction. The
important point is both familial hypercholesterol mutations and a
high polygenic score are associated with more than three-fold
increased odds of an early onset myocardial infarction.


                                               
However, the high polygenic score cannot be reliably identified
on the basis of elevated LDL cholesterol, and yet has a 10-fold
higher prevalence among patients presenting with early onset
myocardial infarction. So very intriguing that both groups
matter.


Dr Greg
Hundley:            
Very good. My next paper is from Adrian Hobbs at the London
School of Medicine, and is looking at the role of endothelial C
type natriuretic peptide as a critical regulator of angiogenesis
and vascular remodeling. We know that a central pathway
coordinating both neovascularization and ischemic extremities in
PAD is driven by vascular endothelial growth factor or VEGF-A4.


                                               
But preclinical studies and other large scale clinical trials
have been disappointing because administering or using VEGF-A to
promote angiogenesis or arteriogenesis in PAD really hasn't
occurred. This group focused on endothelial-derived CMP. Why?
Because it plays a fundamental role in regulating vascular
homeostasis. It controls local blood flow and the resistance
vasculature, and systemic blood pressure, and reduces the
reactivity of leukocytes and platelets.


                                               
So, what were the results? Clinical vascular ischemia was
associated with reduced levels of CMP and it's cognate NPR-C.
Moreover, genetic and pharmacological inhibition of CNP and NPR-C
reduced the angiogenic potential of the pulmonary microvascular
endothelial cells and the human umbilical vein endothelial, and
it isolated vessels ex vivo.


                                               
So, the study really defines a central pathophysiological role
for endothelium-derived C type natriuretic peptide via activation
of cognate natriuretic peptide receptor C in angiogenesis and in
vascular remodeling. Moreover, the work demonstrates the
therapeutic utility of pharmacologically targeting NPR-C to
restore deficits in these processes following ischemia and
injury.


Dr Carolyn
Lam:               
Interesting, from new mechanisms and targets to good, old, major
risk factors for coronary heart disease. Back to the basics but
in a really, I think, nicely done paper from Dr Pencina and
colleagues from Duke Clinical Research Institute.


                                               
Now, their objective in this next paper was to compare the
associations of key, modifiable coronary heart disease risk
factors with incident coronary heart disease events based on
their prognostic performance, the attributable risk fractions and
treatment benefits overall and by age.


                                               
And so really aiming at quantifying the importance of these
major, modifiable risk factors for coronary heart disease. What
they did is they used pool participant level data from four
observational cohort studies sponsored by the NHLBI, and they
created a cohort of more than 22,600 individuals ages 45 to 84
years old who are initially free of cardiovascular disease.


                                               
And these individuals were followed for 10 years from baseline
evaluation and followed for incident coronary heart disease. They
estimated that age, sex and race captured up to 80% of the
prognostic performance of cardiovascular risk models. When we add
either systolic blood pressure or non-HDL cholesterol, diabetes
or smoking to model with the other risk factors, the prognostic
performance, as measured by the C index, increased by only 0.004
to 0.013.


                                               
However, if you look at it from the attributable risk and
absolute risk reduction standpoint, lowering the systolic blood
pressure of all individuals to less than 130, or lowering LDL
cholesterol by 30% would be expected to lower a baseline, 10-year
coronary heart disease risk of 10% to 7% and 8% respectively.


Dr Greg
Hundley:            
That's a lot of data, Carolyn. Help me synthesize all that.


Dr Carolyn
Lam:               
This is a take-home message. Although the individual modifiable
risk factors contribute only modestly to the overall model
prognostic performance, when we eliminate or control these risk
factors, they would actually lead to a substantial reduction in
total population coronary heart disease.


                                               
That's because if we look at the attributable fraction and the
absolute risk reductions, we see that they actually really
matter. The take-home message too from Dr Pencina was that
metrics used to judge the importance of these risk factors should
therefore be tailored to the question being asked.


Dr Greg
Hundley:            
Very good. That was a very nice summary, Carolyn.


Dr Carolyn
Lam:               
Thanks. Let's move on now to our feature discussion, shall we?


Dr Greg
Hundley:            
Very good.


Dr Carolyn
Lam:               
Trials have established that endovascular thrombectomy
dramatically reduces disability after acute ischemic stroke due
to intracranial large vessel occlusion. In fact, guidelines
almost immediately adopted endovascular thrombectomy as a
standard of care. However, that has created some problems.


                                               
The main one being that hospitals equipped to carry out this
procedure are largely limited to tertiary centers in urban areas.
This is, of course, important because that means that patients
may need to be transferred from another center to receive such
treatment.


                                               
Today's feature paper discusses this very issue, a terribly
important one, and I'm so pleased to have the author with us, Dr
Shreyansh Shah from Duke University Medical Center. We have our
editorialist, Dr James Grotta who's director of the Mobile Stroke
Unit project at Memorial Herman Hospital.


                                               
And we have an associate editor, Dr Graeme Hankey from University
of Western Australia. So, such an important topic. I think Shrey,
could you just jump right in and tell us what your study showed.


Dr Shreyansh
Shah:         I'm very
excited to present findings of our study, and as a Carolyn
mentioned, this study is going to have a very important
implication in our country here in US on the creation of systems
of stroke. I think the findings are already applicable to other
countries also where we are seeing endovascular care getting more
and more used.


                                               
As Carolyn was talking, endovascular treatment is very important
and lifesaving measure. But unfortunately, it is not available at
every hospital. Patients are often transferred across different
hospital or institution before they can receive this endovascular
care.


                                               
What we did in our project was we looked at the data from the
hospital that's participating in Get With The Guidelines Stroke,
which is a quality improvement program here in US. It looked at
the endovascular thrombectomy used especially in relation to
inter-hospital transfer.


                                               
What we found was big proportion of patients receiving
endovascular care, up to about 43% to 45% of patients, were
getting the care after transferring across different hospital.
The outcomes in this patient were worse compared to the patient
who were receiving endovascular care if they had come directly to
the hospital.


                                               
While there was no difference in mortality between these two
groups, the endovascular care, after inter-hospital transfer,
resulted in a higher rate of symptomatic ICH, patients are less
likely to be discharged to home, which is the preferred outcome.
And patient was also less likely to be able to ambulate
independently prior to the hospital discharge.


                                               
There was also delay in endovascular care initiation for patient
who received this after inter-hospital transfer. I think this
particular study highlights the magnitude of this problem, and
that's why it's going to be important for people who are studying
systems of care. The fact that about 45% of patient had to get
inter-hospital transfer before endovascular care tells us that we
still need to take significant steps in increasing access to this
lifesaving therapy.


Dr Carolyn
Lam:               
Thank you and indeed James, I really love the editorial you wrote
that accompanied this. I mean you highlighted its importance, and
you also noted that what was unusual about the paper was that
even after controlling for the delay in initiating endovascular
thrombectomy, there was still worse outcomes in the patients who
were transferred. Could you share some thoughts?


Dr James
Grotta:             
It is a very timely issue. Now that we have a very effective
treatment, the big challenge we have is getting it to the
patients as fast as possible. Right now, our system, as is
pointed out, means shuffling patients from one hospital to
another.


                                               
I think that clearly with stroke treatment, any sort of stroke
treatment, the faster we deliver it, the better. Other studies
have shown that transferring patients is associated with a delay
of treatment, and this study showed the same thing.


                                               
There was a substantial delay in getting the patients treated if
they required a transfer. And as you pointed out, however, this
did not explain the entire or was not at least the entire
explanation for the worst outcome. So, it is a little bit of a
mystery.


                                               
I do know from personal experience that transferring patients
from hospital to hospital, it's not exactly a black hole, but you
lose control of the patient when they're being transferred. These
are patients who have large artery occlusions. That means they
have their middle cerebral artery is blocked.


                                               
And so, the area of brain that's affected is in a very tenuous
shape. So, any drop-in oxygen concentration from breathing
problems or of any drop-in blood pressure might further worsen
the stroke. So, this could happen in transit. So, it's possible
that in the process of transfer, these sorts of things happen.


                                               
I do think that we do have to be a little bit careful in that by
remembering that this was not a randomized comparison, so
patients that were treated directly and those that were
transferred were not randomized. And so, although they appear to
be balanced in a lot of the important variables like their stroke
severity, there may be other things that we can't account for
that could explain some of the worst outcomes.


                                               
I'd like to ask Dr Shah whether he identified any things in ...
well, he and his co-authors think might have contributed to some
of the worst outcomes.


 Dr Shreyansh
Shah:        To answer Dr
Grotta's question about what other factors may have played a role
in the worst outcome that we saw in patients who were getting
inter-hospital transfer, I think as we correctly pointed out,
transferring this very sick patient is very tricky. As we know,
the hemodynamic instability or variability plays an important
role in outcomes of stroke patient.


                                               
And it is very likely that during the transfer process, there is
not adequate control of their blood pressure variability, their
oxygen saturation, and this ends up affecting their brain leading
to worst outcome. The other possibilities also, as Dr Grotta was
explaining, this is not a randomized control trial.


                                               
And although we balance for number of important factors that can
affect stroke outcome, there might be a selection bias in
transferring patient who are more sicker and also patients who
received thrombolysis with TPA but did not improve, while the
patient who were directly arriving to the hospitals and getting
endovascular care, they received the TPA.


                                               
It is possible that they started to improve and still received a
thrombectomy at the same time. So that group may have been more
favorable in that respect, which could have also played a role in
better outcomes with patient who are directly arriving.


Dr Carolyn
Lam:               
Interesting. And, you know, with the mention of TPA, I really
have to bring James back. I loved your mention about potential
solution using mobile stroke units. And since you direct one of
them, could you tell us what you meant there?


Dr James
Grotta:             
Yes, of course, I have to state at the outset that I have a
little bit of a bias about mobile strokes, and so I do it every
day. What a mobile stroke unit is, for those who don't know, it's
basically taking the emergency department to the patient.


                                               
It's an ambulance with a CT scanner on board and the ability to
treat with TPA in the field. But in addition, it's also the CT
scanner. We can do CT angio and identify large vessel occlusions
on the mobile stroke unit, not to mention the fact that you have
a vascular neurologist either in-person or by telemedicine
examining the patient.


                                               
So clinically, you can make the determination also much more
accurately than any sort of pre-hospital stroke scale, whether
the patient has a large artery occlusion. That way, you don't
have to take the patient to the nearest hospital. You can bypass
the nearest hospital, take them right to the thrombectomy center,
therefore, avoiding the transfer process.


                                               
We've been implementing this in Houston, and there are now about
30 mobile stroke units around the world. The innovation actually
started in Germany by Dr Fassbender about a decade ago in
Hamburg, Germany. We are conducting a randomized trial, comparing
mobile stroke unit care to standard management to see how much
better outcomes occur as a result of this faster treatment.


                                               
We obviously can treat patients with TPA faster. For example, a
similar study from the Get With The Guidelines a few years ago
showed that only 1% of patients treated with TPA in emergency
departments get treated within the first hour after symptom onset
simply because it takes an hour in the emergency room itself to
do the evaluation of the patient and get them treated.


                                               
Whereas on our mobile stroke unit, at least a third and probably
40% of the patients we're treating with TPA, we can get treated
within that first hour where there may be an exponential better
benefit. But we don't yet know really how much that translates to
better benefit, and also, of course, mobile stroke units are more
intensive in terms of the amount of facilities on board and
costs.


                                               
So, we need to look at the cost-effectiveness. If it produces
only a marginal reduction in disability but costs a fortune, then
it's not worth it. But in fact, in our experience, it's pretty
practical. We can cover almost the entire City of Houston, which
is the fourth largest city in the country, with one mobile stroke
unit. When it's well-integrated, it requires careful integration
with the fire department and other hospitals in the city.


 Dr Shreyansh
Shah:        At those two
conferences, I came across a very interesting talk from Dr
Grotta's group about rendezvous with the EMS which allows
extending their coverage area significantly. I think we
definitely need more and more innovative solutions like this
where we can identify patients by their origin, whether they have
large vessel occlusion or not, and then triage them appropriately
at the centers that can perform endovascular therapy. So as a
result, we can provide them earlier therapy and hopefully, it
will lead to better outcome.


Dr Carolyn
Lam:               
Thank you Shrey and James for these incredible insights. Now,
Graeme, I want you to have the last word and reflections from
down under.


Dr Graeme Hankey:       
Firstly, just to congratulate Dr Shrey and colleagues on this
terrific study that reports a contemporary United States
experience, a very broad one across the country, really
highlighting how since 2012, until a year ago, there's been a
six-fold increase in the number of patients being transferred for
endovascular therapy.


                                               
And we're all experiencing that around the world. And moreover,
since the DAWN trial and the DEFUSE trial were published just
over a year ago, which is when this study stopped, there's been
an expansion of the window from six hours out to 24 hours.


                                               
So, in the last year, which this study doesn't cover, we've seen
an exponential increase in the number of people being transferred
from rural and remote areas who have had a stroke up to 24 hours
ago being considered for endovascular therapy if their CT
angiogram at the base hospital shows a large vessel occlusion.


                                               
This is likely to be not only internally valid, but externally
valid to all of us around the world. It reflects our experience
of this avalanche of cases coming. And it's provided a lot of
challenges for those who are trying to deliver the service at the
tertiary referral center.


 
                                             
And it highlights that nearly half of the cases who are having
endovascular therapy are coming from external sites. As Jim has
really highlighted in his editorial, it challenges us to reassess
the current practice of inter-hospital transfer.


Dr Carolyn
Lam:               
Thank you so much for publishing this paper with us and the
editorial. And listeners, don't forget to tune in again next
week. This program is copyright American Heart Association, 2019.