Circulation May 29, 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.


                                               
What do salty, Chinese meals, neurotransmitters, cancer, and
pulmonary arterial hypertension have in common? Well, you are not
going to want to miss this week's feature discussion. It's going
to reveal a new therapeutic approach to pulmonary arterial
hypertension that may just surprise you, coming up right after
these summaries.


                                               
Do congenital heart defects signal a familial predisposition to
cardiovascular disease? Well, this question was addressed in this
week's first original paper from first and corresponding author,
Dr. Auger, from University of Montreal Hospital Research Center
in Quebec, Canada. Dr. Auger and colleagues aimed to determine
whether the risk of cardiovascular disorders later in life was
higher in women who had newborns with congenital heart defects.
To answer the question, they studied a cohort of more than one
million women who had delivered infants between 1989 and 2013 in
Quebec. They showed for the first time that congenital heart
defects in offspring were associated with increased risk of
maternal cardiovascular morbidity later in life, including
atherosclerotic disease, cardiac hospitalization, and cardiac
transplantation. The association with subsequent cardiovascular
morbidity risk was present for both critical and noncritical
congenital heart defects. Thus, women who have given birth to
offspring with congenital heart defects may benefit from early
attention to traditional cardiovascular risk factors and more
aggressive primary prevention strategies.


                                               
Acute myocardial infarction, or AMI, is a major cardiovascular
complication of non-cardiac surgery, but what are the outcomes
following perioperative AMI? This question was answered in the
next paper from co-corresponding authors, Dr. Smilowitz and
Berger, from New York University School of Medicine. The authors
identified more than 8,000 patients who were diagnosed with AMI
during hospitalization for major non-cardiac surgery using the
2014 US Nationwide Readmission Database. They found that
perioperative AMI after non-cardiac surgery was associated with a
high in-hospital mortality and a 19% risk of 30-day hospital
readmission among survivors. The majority of hospitalizations
after perioperative AMI were because of infectious,
cardiovascular, or bleeding complications. Recurrent AMI occurred
in 11% of patients re-hospitalized after perioperative AMI. At
six months after perioperative AMI, more than 36% of patients
were re-hospitalized, and the overall risk of in-hospital deaths
was almost 18%. Thus, hospital readmissions and mortality among
patients with perioperative AMI pose a significant burden to the
healthcare system. Strategies to improve outcomes of surgical
patients early after perioperative AMI are warranted.


                                               
What is the recent status of hypertension in China?
Co-corresponding authors, Dr. Wang and Gao, from Fuwai Hospital,
Peking Union Medical College, and Chinese Academy of Medical
Sciences in China used a stratified, multistage, random sampling
method to obtain a nationally representative sample of more than
450,000 residents from 31 provinces in mainland China from 2012
to 2015. The authors found that more than 23% of Chinese aged 18
years or old had hypertension, and that's equivalent to an
estimated 284.5 million individuals. The prevalence of
hypertension was similar in rural and urban settings, whereas
three municipalities, mainly Beijing, Tianjin, and Shanghai had
the highest prevalence of hypertension. Almost half the
hypertensive population was aware of their hypertension. About
41% were treated, and only 15% achieved a blood pressure control.
Among treated patients, barely 32% were prescribed two or more
antihypertensive medications. Thus, this study revealed a
considerable prevalence of hypertension in Chinese adults, as
well as low awareness and control rates, representing an urgent
public health message in China.


                                               
Patients with systemic sclerosis-associated pulmonary arterial
hypertension have a far worse prognosis than those with
idiopathic pulmonary arterial hypertension. But why is this the
case? In the next paper, from co-corresponding authors, Dr. Hsu
and Dr. Kass, from Johns Hopkins University School of Medicine,
these authors tested whether the disparity involved underlying
differences in myofilament function. They studied cardiac
myocytes isolated from the right ventricular septal
endomyocardial biopsies from patients with systemic
sclerosis-associated pulmonary arterial hypertension, idiopathic
pulmonary arterial hypertension, or systemic sclerosis with
exertional dyspnea but without pulmonary arterial hypertension.
They also looked at control right ventricular septal tissue
obtained from non-diseased donor hearts.


                                               
They found that right ventricular myofilaments isolated from
humans with systemic sclerosis-associated pulmonary arterial
hypertension exhibited diminished contractile force and abnormal
calcium sensitivity versus control myofilaments. This is in sharp
contrast to the hypercontractile compensation in idiopathic
pulmonary arterial hypertension. Systemic sclerosis patients with
dyspnea and only exercise-induced pulmonary hypertension
exhibited an intermediate right ventricular myocardial filament
phenotype. These myofilament contractile abnormalities correlated
strongly with in vivo right ventricular function at rest and
right ventricular contractile reserve during exercise, suggesting
a central role of right ventricular myofilament dysfunction in
systemic sclerosis-associated pulmonary arterial hypertension.


                                               
In summary, these findings uncover key deficiencies in the right
ventricles of systemic sclerosis-associated pulmonary arterial
hypertension, and these findings suggest that therapies targeted
at right ventricular myofilament contractile dysfunction may
prove particularly useful for this vulnerable subpopulation. That
wraps it up for our summaries. Now, for our feature discussion.


                                               
Today's feature paper promises a new therapeutic approach in
pulmonary arterial hypertension. We know that pulmonary arterial
hypertension is a rare disease, but nonetheless it casts a large
shadow because it most commonly afflicts young women and remains
a disabling disease. Despite treatment advanced in the last 20
years, high-risk patients still succumb at a rate of 15%
annually. Moreover, our most effective therapy is a continuous
infusion of parenteral prostacyclin, which is both cumbersome and
expensive. Thus, there remains an urgent need for better
therapies to improve survival and quality of life. Today's
feature paper introduces a novel approach to this.


                                               
I'm so pleased to have the corresponding author, Dr. Sylvia
Cohen-Kaminsky, from Inserm, Paris, France, as well as associate
editor Dr. Charlie Lowenstein, from University of Rochester, to
discuss today's special paper. You know, I'm gonna start with
Charlie, because you have a way of explaining things and just
putting the background to mechanistic papers so well. Could you
do that for us, please?


Dr Charlie Lowenstein:  Sure. When I started in research, I
worked in a neuroscience laboratory. One of the things we studied
was glutamate and its class of receptors. Glutamate, as you know,
is one of the major neurotransmitters in the brain. The brain
releases small amounts of glutamate, which acts as a messenger,
neurons talking to other neurons. But when there's a stroke, the
brain releases huge amounts of glutamate, and it's actually toxic
and can cause damage, and mediate neuronal damage and cell death.
Glutamate is a hot topic in the world of neuroscience. But in the
cardiovascular field, people don't know much about glutamate.
They don't appreciate glutamate as being important at all. So, I
have a question for you, Sylvia. How did you start to get
interested in glutamate and its family of receptors?


Dr Sylvia
Cohen-Kaminsky:         
It started around 2000, and since 2000 we are having some clues
about peripheral glutamate receptor in different cells in
different organ. But basically, for vascular cells and for the
topic of PAH, there was two things that make me thought about it.
First of all, it was shown that the NMDA receptor contributes to
the proliferation of different cancer cell types. Human tumor
cells express the NMDA receptor, then an NMDA-receptor antagonist
may inhibit cancer cell growth and migration. We know that
pulmonary vascular cells from PAH patients have cancer-like
properties. They are also proliferative and resistant to
apoptosis, and they have several properties of cancer cells, such
as metabolic shift and so on.


                                               
In addition, not only neurons in the brain express the NMDA
receptor, but also brain microvascular endothelial cells that
respond to an NMDA receptor activation by gross production,
disruption of endothelial cell barrier, and monocyte
transmigration. All these three processes are relevant to PAH
development. That's why I thought that perhaps an NMDA receptor
is expressed on microvascular cells from the lung, and perhaps we
could have a process involving an NMDA receptor in this vascular
remodeling.


Dr Charlie Lowenstein:  As you know, there are three flavors
of glutamate receptors. How did you discover that there was one
particular kind, the NMDA receptor, that was really important for
smooth muscle cells?


Dr Sylvia
Cohen-Kaminsky:         
You are right. We did analysis of mRNA expression, and most of
the known receptor in the brain, either metabotropic or ...
ionotropic, sorry, indeed expressed in vascular cells and they
may cooperate to activate this NMDA receptor exactly as it
happens in the brain. We didn't work that on these other
receptor, but we are pretty sure they are at work in cooperation
with the NMDA receptor. Why though an NMDA receptor? Because it's
an ion channel permeable to calcium, and the calcium is an event
which can be important in cell proliferation. In addition, the
first thing we have shown in these remodeled vessels when we did
mass spectrometry imaging was increased level of glutamate and
glutamine, its precursor. That was also an additional element
that makes us think about this NMDA receptor.


Dr Charlie Lowenstein:  I want to go from the receptor to
glutamate. There are three or four amazing things about your
paper. One of them is that you suggest that cells in the vascular
are releasing glutamate, which is a neurotransmitter. Do you
think those are the smooth muscle cells that are talking to other
smooth muscle cells by releasing these messenger molecules?


Dr Sylvia
Cohen-Kaminsky:         
Yes. Smooth muscle cells are talking to other smooth muscle
cells. But we also did some work on endothelial cells, and they
are also able to release this glutamate. So we think that
vascular cells in the vascular wall are discussing together
through glutamate, although we don't know yet the normal function
of this NMDA receptor in the vascular system. However, in the
pathology it's very clear that there is this release. What is
very interesting is that this release can be triggered by
pathways which are already down-regulated in PAH, such as the
endothelin-1 pathway.


Dr Charlie Lowenstein:  Another remarkable part of your
observation is that the signaling with glutamate and glutamate
receptors is hyperactivated in the setting of a major human
disease, pulmonary artery hypertension. How did you figure out
that glutamate is so important in this special disease?


Dr Sylvia
Cohen-Kaminsky:         
Because we showed, as I already told you, this glutamate
accumulation in the remodeled vessel. We used this mass
spectrometry imaging which allows analysis of metabolites
directly in the remodeled vessels from sections performed from
extended lengths. We saw this glutamate accumulation together
with glutamine accumulation, so the ligand was overexpressed. In
addition, when doing western blots from these remodeled tissue
dissected from ongoing arteries, we have shown that we have a
particular phosphorylation of this receptor which is very
well-known in the CNS. This phosphorylation is involved in
sending the receptor to the membrane and stabilizing the receptor
to the membrane. Having this phosphorylation means that NMDA
receptor is engaged, activated in the remodeled vessels in situ.


Dr Charlie Lowenstein:  In an experimental model, you
explored the role of glutamate in two very nice, complementary
ways. One is with a genetic approach, the NMDA receptor
deficiency. The other is using drugs. What were the drugs, what
were the pharmacology that you used to block glutamate's
transmission, and how did that affect the mice?


Dr Sylvia
Cohen-Kaminsky:         
We used drugs that are very well known in the CNS. We used two
drugs. One is memantine, which is already commercialized for the
treatment of Alzheimer's disease. The other one is MK-801, which
has been produced initially as a potential pharmacological drug
but it was too potent to be used in the CNS. Therefore, this drug
is only used in research at the moment. But these two drugs were
able to act on this vascular remodeling and a number of PAH
parameters. We have explored at least 12 parameters involved in
this animal model of PAH, and hemodynamic stable parameters of
hemodynamics including intra-arterial pressure, vascular
remodeling, right ventricular remodeling with different
parameters that shows a certain index. The cardiomyocyte
hypertrophy, the fibrosis, the inflammation inside the right
heart and around remodeled vessels, all these parameters were
modified by the drug.


                                               
In addition, in vivo we have shown the destruction of the NMDA
receptor glutamate axis with decreased engagement of the NMDA
receptor in pulmonary arteries by following this phosphorylation
I mentioned, decrease of apoptosis resistance and also
proliferation. This was shown also after the treatment with the
drugs, and also decrease of endothelial cell dysfunction that
could be followed in the blood through selecting those H.


Dr Charlie Lowenstein:  Your results with this drug were
really impressive. I love that part of your study. You showed
when you block glutamate signaling, first of all, the blood
vessels looked much better in a model of pulmonary artery
hypertension. In an experimental model, blocking glutamate
transmission really improved the way the vessels look. But
secondly, what was really amazing was, normally in humans one of
the big problems with pulmonary artery hypertension, as you said,
is the right ventricle gets inflamed and fibrotic, and a lot of
patients die from complications of right ventricular dysfunction.
In your model, when you treat with MK-801, blocking glutamate
receptor, the right ventricle looks a lot better. It was really
an impressive part of your study.


Dr Sylvia
Cohen-Kaminsky:         
I think that this is view on the effect of the vessels
themselves, then the right heart can recover. But we may have a
direct effect in the heart. If you remember this Chinese
restaurant syndrome, when you eat too much Chinese food, which is
full of glutamate, you have some cardiac involvement, arrhythmia,
and so on. Initially, toxicologists thought that it passed
through the central nervous system. But then they realized that
maybe the NMDA receptor is expressed in cardiac cells, and indeed
it is expressed and is colocalized with the ryanodine receptor,
meaning that it could have a function in the heart as well. But
this has, of course, to be explored precisely. We know from the
transplantation that, when we transplant on with the lung, the
heart can recover very well. We may have these two effects. One
due to the relief on vascular remodeling, and the other perhaps a
direct effect on the heart.


Dr Carolyn
Lam:               
You know, I have to chime in now. That cuts too close to home
with the Chinese food and glutamate. First and foremost, I just
really have to say, Charlie and Sylvia, it's people like you who
make basic science come alive and simply extraordinarily
exciting. Taking glutamate, something that we've talked about in
the context of Chinese food and neurotransmitters, and therefore
showing the potential to even repurpose perhaps some drugs for
pulmonary arterial hypertension. So let me just round up by
asking you, what do you think our next steps, how far are these
findings away from clinical application? Perhaps, Charlie, your
thoughts?


Dr Charlie Lowenstein:  While I think that the use of MK-801
to treat excess monosodium glutamate during a Chinese meal, maybe
that's a little bit premature. I'm much more excited about the
idea of using glutamate-receptor antagonists to treat or prevent
or even reverse pulmonary artery hypertension, both its vascular
and cardiac complications. I'd love to ask Sylvia, do you think
these medications in this class, do you think NMDA-receptor
antagonists are ready for clinical trials?


Dr Sylvia
Cohen-Kaminsky:         
In fact, they are not ready as they are. We have a program in
which we have designed hypothesized new NMDA-receptor antagonist
that do not go to the brain, because we want that treating PAH
has to be safe, and we don't want to interfere with brain system.
So we created this new NMDA-receptor antagonist that do not go to
the brain. At the moment, we are in the process of the
documentation. We have two patents for two series of molecules,
and we expect the drug conjugate by the end of this year. To
reconjugate means that we have a number of properties on this
drug, the pharmacokinetics, metabolism, selectivity profile,
toxicity, and so on. We are doing all this physical chemical
properties, and of course validation of these new molecules in
the animal models as therapy alone and also as add-on therapy
with existing therapies, such as these vasodilators. We hope that
we can have an additive effect between an NMDA-receptor
antagonist and current PAH drugs.


Dr Charlie Lowenstein:  Sylvia, as you know, drug companies
about 10 or 20 years ago invented all these amazing
glutamate-receptor antagonists to treat central nervous disease
like stroke. One of the amazing things about your discovery is
you're suggesting that glutamate receptors in the periphery are
great targets as well. The exciting thing about your observation
is you're really opening up new therapeutic approaches for
targeting neurotransmitters in the periphery. I think your
discoveries are tremendously exciting and could open up new
avenues in treatment of a disease, pulmonary artery hypertension,
for which there really aren't effective therapies right now.


Dr Carolyn
Lam:               
I couldn't have said it better. Thank you so much, Charlie. Thank
you so much, Sylvia.


                                               
See, listeners? Aren't you glad you heard it here right on
Circulation on the Run? Don't forget to tune in again next week.