Circulation August 15, 2017 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 podcast today
highlights an important perspective piece on charting a future
together and turning discovery science into cardiovascular
health. You don't want to miss this, coming up right after these
summaries. The first original paper tells us about the importance
of changes in exercise capacity following transcatheter aortic
valve replacement or TAVR.


                                               
First author, Dr. Altisent, corresponding author, Dr.
Rodés-Cabau, and colleagues from Quebec Heart and Lung Institute
in Canada studied a total of 305 patients undergoing TAVR with
baseline and six month followup exercise capacity assessments by
six minute walk tests. They found that close to one-third of
patients undergoing TAVR failed to improve their exercise
capacity despite an optimal hemodynamic result post-procedure.


                                               
Factors associated with a lesser exercise capacity improvement
included patient characteristics such as older age, female sex,
non-cardiac comorbidities, such as chronic obstructive lung
disease, peripheral artery disease and bleeding episodes
resulting in reduced hemoglobin levels. Importantly, the absence
of an improvement in physical performance at six months post-TAVR
was an independent predictor of mortality and adverse
cardiovascular outcomes during the ensuing four years and
particularly among patients with a greater impairment of exercise
capacity pre-TAVR.


                                               
Thus, implementing exercise capacity assessment pre and post-TAVR
may help to improve patient risk stratification and augment the
accuracy of the prognostic information given to patients, helping
to identify those requiring more intensive followup assessment.
The next study provides mechanistic insights into the adverse
health outcomes associated with particulate matter exposure in
the air. First author, Dr. Lee, corresponding author, Dr. Kahn,
from Fudan University in Shanghai, China and colleagues conducted
a randomized double-blind crossover trial in 55 healthy college
students in Shanghai. Real and sham air purifiers were placed in
participant's dormitories in random orders for nine days with a
12 day washout period.


                                               
Serum metabolites were quantified using gas chromatography mass
spec and ultra-high performance liquid chromatography mass spec.
They found that higher particulate matter exposure led to a
significant increase in cortisol, cortisone, epinephrine and
norepinephrine. Between treatment, differences were also observed
for glucose, amino acids, fatty acids and lipids. They also found
that higher blood pressure, hormones, insulin resistance and
biomarkers of oxidative stress and inflammation were present
among individuals with higher exposure to particulate matter.


                                               
Thus, this study showed that activation of the
hypothalamus-pituitary-adrenal and sympathetic-adrenal medullary
axis may contribute to the adverse cardiovascular and metabolic
effects of particulate matter exposure in the air. In China,
indoor air purification may be a practical way to reduce personal
exposure to particulate matter. The next study shows that
N-acetylcysteine may be new effective thrombolytic treatment.
First author, Dr. Lizarrondo, corresponding author, Dr. Gauberti
and colleagues from Inserm, France hypothesized that
N-acetylcysteine might cleave the von Willebrand factor multimers
inside occlusive thrombi, thereby leading to their disillusion
and arterial recanalization.


                                               
To test this hypothesis, the authors used experimental models of
thrombotic stroke induced by either intra-arterial thrombin
injection or ferric chloride application followed by measurement
of cerebral blood flow using a combination of Laser Doppler
Flowmetry and magnetic resonance imaging. They showed that
intravenous and acetylcysteine administration promoted lysis of
arterial thrombi that were resistant to conventional approaches
such as recombinant TPA, direct thrombin inhibitors and
anti-platelet treatments. Furthermore, through in vitro and in
vivo experiments, they provided evidence that the molecular
target underlying the thrombolytic effects of N-acetylcysteine
were principally the von Willebrand factor that crosslinked
platelets in arterial thrombi.


                                               
Co-administration of N-acetylcysteine and a non-peptidic GP2B3A
inhibitor further improved its thrombolytic efficacy essentially
by accelerating thrombus disillusion and preventing rethrombosis.
In a new large vessel thromboembolic stroke model in mice, this
co-treatment significantly improved ischemic lesion size and
neurological outcomes. Importantly, N-acetylcysteine did not
worsen hemorrhagic stroke outcome suggesting that exerted
thrombolytic effects without significantly impairing normal
hemostasis. Thus, in summary, N-acetylcysteine was shown to be an
effective and safe alternative to currently available
anti-thrombotic agents to restore vessel patency after arterial
occlusion.


                                               
The clinical implications of the study are wide reaching
considering the very wide availability, low cost and apparent
safety of N-acetylcysteine. This is discussed in an accompanying
editorial by Dr. Lillicrap from Queens University, Kingston,
Canada. The final study identifies a novel mechanism for
regulation of cardiac fibrosis that revolves around plasminogen
activator inhibitor type 1 or PAI-1. First, author, Dr. Flevaris,
corresponding author, Dr. Vaughan and colleagues of Northwestern
University, Feinberg School of Medicine in Chicago, Illinois
showed that cardiac fibrosis was detected by late gadolinium
enhancement cardiac MRI in two otherwise healthy humans with
complete PAI-1 deficiency due to a homozygous frameshift mutation
in serpene 1.


                                               
They further performed a series of mouse experiments to show that
treatment of young PAI-1 deficient mice with angiotensin 2
induced extensive hypertrophy and fibrotic cardiomyopathy.
Ventricular myocytes were found to be the important source of
cardiac transforming growth factor beta or TGF beta and PAI-1
regulated TGF beta synthesis by cardiomyocytes in vitro as well
as in vivo during cardiac injury. PAI-1 deficiency significantly
enhanced multiple TGF beta signaling elements and transcriptional
targets. Thus, in summary, this study show that PAI-1 is an
essential repressor or cardiac fibrosis and access a molecular
switch that controls the cardiac TGF beta access and its early
transcriptional effects that lead to myocardial fibrosis.


                                               
Modulation of the cardiomyocytes TGF beta access represents a
unique therapeutic strategy that may abrogate fibrotic signaling
and cardiac fibrosis. Well, that wraps it up for your summaries.
Now for our featured discussion. We are incredibly privileged
today to have the director of the National Heart, Lung and Blood
Institute, Dr. Gary Gibbonss with us on the podcast, as he talks
about his perspective piece entitled "Charting Our Future
Together: Turning Discovery Science into Cardiovascular Health."
Also, joining me today is our editor in chief, Dr. Joseph Hill
from UT Southwestern. Joe, I know you share my incredible
excitement and enthusiasm at having Dr. Gibbonss on this podcast
with us.


                                               
Maybe could I invite you to say a few words to frame just how
important this perspective piece is for Circulation?


Dr. Joseph
Hill:                  
We all know that cardiovascular medicine and science are evolving
at an unprecedented pace. The challenges we face are evolving and
yet the opportunities and the tools and the resources at our
disposal are unprecedented in their scope and vision. We're very
pleased that Gary has provided strong leadership at NHLBI now for
several years and has laid out in this perspective piece here
where he thinks the next steps are specifically around this
strategic vision that focuses on precision medicine and data
science. I would love to hear Gary provide additional perspective
on that vision.


Dr. Gary
Gibbons:           
Well, thank you, Joe. As the director of NHLBI, clearly we're
public servants and we're accountable stewards of the nation's
investment in heart, lung and blood and sleep disorders. This
piece gave us an opportunity to outline some of the opportunities
that lay ahead in a strategic visioning process. First, I should
note that a key part of the legacy of the NHLBI is to make
strategic investment with enduring principles in mind to really
support investigator initiated discovery science as really the
core foundational element of our research portfolio, as well as
to maintain a balance portfolio to really expands to spectrum of
basic translation clinical population and implementation science.


                                               
In this piece, we particularly want to highlight our strategic
visioning process in which we encourage the broad input of the
NHLBI community that actually included over 4,000 participants in
this process from every state in the country. Indeed, 42
countries around the world to provide the most compelling
questions and critical challenges that the field faces around
strategic goals of understanding normal human biology, reducing
disease, accelerating translation and preparing a biomedical
workforce and resources for the discovery science of the 21st
century.


                                               
Out of that strategic vision, we focus in on two elements that
emerged that relate it to precision medicine and data science for
this piece and really that was the central core of what we wanted
to share with the Circulation readership about how these two
areas we think are going to be transformative in the years ahead.


Dr. Carolyn
Lam:              
Dr. Gibbons, you know, when the term precision medicine is used,
sometimes it's a bit fuzzy I think in the minds of a lot of
people. Could you maybe give a few examples or perhaps a specific
idea that comes to mind?


Dr. Gary
Gibbons:           
You're right. There's often a lot said about it than probably a
bit of hype about it. In some ways you could see this as a legacy
of cardiovascular medicine and science. It could be argued that
the definition of cardiovascular risk factors that came out of
the Framingham Heart Study many years ago was the first sort of
forerunner of precision medicine. It helped us indeed define
those individuals who are at the greatest risk of having a heart
attack and that to this day has played a role in directing
targeted preventive treatments of the highest risk individuals in
order to prevent heart attacks. That has continued to evolve.


                                               
I think what's new now is that we have, as Dr. Hill mentioned,
new modalities of both imaging and analytics of computational
science, as well as novel biomarkers and genetic markers that can
help us be even more precise in that risk assessment. That's
really I think the greater opportunity to further subcategorize
patient populations to get the right drug to the right patient at
the right time with a more strategic treatment approach.


Dr. Joseph
Hill:                  
Gary, that's very exciting. I think your vision is absolutely
compelling. I like how you categorize the NHLBI as a catalyst for
the future. I'd like to think that the Biomedical Journals, the
AHA Portfolio of Journals and Circulation are also catalysts that
will partner with NHLBI and other entities to chart the course
for the future. That again the challenges that we face now are
different than they were back in the era when Framingham first
got started after World War II. The tools that we have are also
evolving rapidly and certainly our perspective from Circulation
is that we are stewards of helping chart that course, helping
identify and bring forth the best science around the world. In
many ways we look to you as a partner.


Dr. Gary
Gibbons:           
Oh, absolutely. The NHLBI really can't fulfill our mission of
turning discovery science into the health of the nation and
indeed around the world without a circle of partners and that
certainly includes the platforms of disseminating new knowledge
like Circulation, as well as partner organizations such as
American Heart Association. We definitely appreciate the value
that your organ brings to really enhancing our efforts to not
only take discovery science, but make that knowledge available to
practitioners and researchers and patients.


                                               
I think a key part of the 21st century is how we not only can
discover and generate new knowledge, but how we can facilitate
that movement of data to knowledge and from knowledge to action
that actually enhances the lives of patients in the real world
context. Again I believe your journal plays an important role in
helping to do that.


Dr. Carolyn
Lam:              
You both mentioned critical challenges that we're facing and will
face. The Chinese for these challenges or crisis, the word is
actually wéijī. Okay? Wéi is actually meaning danger, whereas jī
is for jīhuey which is opportunity. In every challenge, there's
always this new opportunity and I just really would like to ask
what are the greatest challenge and perhaps the greatest
opportunity?


Dr. Gary
Gibbons:           
I think the challenge that we probably face is the emerging
epidemic of non-communicable diseases typically cardiovascular
disease throughout the world. Not only in the most industrialized
nations, but indeed mainly the developing nations. This will
quickly surpass communicable infectious diseases as the major
burden and causes of mortality worldwide. We're dealing with a
global challenge. Increasingly, we recognize that scientific
discovery and analysis is often siloed in various packets. Our
vision for the future is really to promote the creation of a
global reach of what we're calling a Data Commons. That is that a
disease has no borders. Science should not be limited to national
states.


                                               
It is part of the commonwealth if you will of information and
knowledge that really should transcend national borders. We say
this is a global community of data and information and knowledge
exchange and collaboration. As part of this global community,
it's that we think this diverse and inclusive approach will be
critical to the best minds and best practitioners of the world
learning from each other and contributing to this commonwealth of
knowledge. We're excited because the opportunity on the other
side of that challenge is that it's an unprecedented capability
of power to communicate now. We I think are communicating with
you from Singapore and we're in a digital age in which this
notion of communication and knowledge exchange should be more
fast than it's ever been before.


                                               
Indeed, we can create computer platforms that are similar to what
exist for a Facebook or a Google that are global in scope. The
vision is really to say what would happen if we could turn that
toward biomedicine and make biomedicine part of this data science
such that we have global contributions to our understanding,
knowledge exchange and really create that sort of global sandbox
if you will of knowledge exchange and discovery. That's part of
this notion of creating a Data Commons and really advancing data
science as an element of a strategic vision.


As we move forward with precision medicine and data science, our
most sacrosanct stewardship is for the next generations. A
critical element is to ensure that we're providing them with the
tools and training to really lead the charge of advancing these
exciting areas of science and that indeed will be a global
enterprise.


Dr. Joseph
Hill:                  
That's very exciting, Gary. I take my hat off to you for the
leadership that you have maintained at the NHLBI during these
times that are once very challenging and at the same time
exhilarating. I look forward to working with you through our
journal and partnering with you to bring to fruition much of what
you had laid out in your vision.


Dr. Gary
Gibbons:           
Thank you, Joe. We look forward to our ongoing partnership.


Dr. Carolyn
Lam:              
Thank you, listeners, for joining us today. Do join us again next
week.