Circulation October 24, 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. Today's feature discussion
centers on the population burden of sudden death associated with
hypertrophic cardiomyopathy. These are novel data from the
ongoing Oregon sudden unexpected death study, results that may
surprise you. Stay tuned and that's coming up right after these
summaries.


                                            
The first original paper in this week's journal tells us that
risk reductions from air pollution control yields health benefits
comparable to the control of systolic hypertension and smoking in
a high risk segment of the urban Chinese population. First author
Dr Huong, corresponding author Dr Gu and colleagues from Fu-Wai
hospital in Beijing China projected the life years gained if
urban China were to reach one of three air quality goals. First,
Beijing Olympic games level. Second, China class 2 standard.
Third, the WHO standard. They further compared projected air
pollution reduction control benefits with the potential benefits
of reaching WHO hypertension and tobacco control goals.


                                            
Now to do this, the authors used the Cardiovascular Disease
Policy Model: China, which is a computer simulation state
transition mathematical model of coronary heart disease and
stroke incidence, prevalence, mortality, non-cardiovascular
deaths, and costs of health care in the Chinese population. They
found that air quality improvement under the different scenarios
could lead to a great health benefit, ranging from 241,000 life
years gained to much greater benefits, benefits that were greater
to or equal to the combined benefits of a 25% improvement in
systolic hypertension control, and a 30% smoking reduction. Thus,
the authors called for joint efforts of the whole society for air
quality improvement in China.


                                            
The next study describes six differences and similarities in
atrial fibrillation epidemiology, risk factors, and mortality in
the community. First author Dr [Magnusson 00:02:42],
corresponding author Dr [Schnabel 00:02:44] and colleagues from
University Heart Center Hamburg Eppendorf studied 79,793
individuals without atrial fibrillation diagnosis at baseline
from 4 community-based European studies, namely, FINRISK,
DanMONICA, Molisani, and Northern Sweden, all followed for a
medium of 12.6 years. They found that cumulative incidence
increased markedly after the age of 50 years in men and after the
age of 60 years in women. The lifetime risk was similar in more
than 30% for both sexes.


                                            
Subjects with incident atrial fibrillation had a three and a half
fold higher risk of death compared with those without atrial
fibrillation. Among the classical risk factors, body mass index
explained the largest proportion of atrial fibrillation risk. Six
interactions were seen for the risk associations of body mass
index and total cholesterol, wherein body mass index was
associated with a greater risk increase in men than women,
whereas total cholesterol was inversely associated with incident
atrial fibrillation with a greater risk reduction in women than
men.


                                            
The next study describes a novel circular RNA as a potential
target in diabetic proliferative retinopathy. Circular RNAs are a
novel class of non-coding RNAs that regular gene expression and
they're characterized by closed loop structures with neither
five-prime, nor three-prime polarity nor a polyadenylated tail.
In today's study, first author Dr [Shah 00:04:33], corresponding
authors Drs. [Yen 00:04:33] and [Zhao 00:04:36] from Shanghai
Medical College Fudan University in China characterized the
expression and regulation of the circular RNA, circHIPK3 in
retinal endothelial cells and diabetic retinal vascular
dysfunction.


                                            
CircHIPK3 expression was significantly up regulated upon high
glucose stress in vivo and in vitro and regulated retinal
endothelial cell function and vascular dysfunction by acting as
an endogenous microRNA 30A-3P sponge that sequestered and
inhibited its activity. In summary therefore, the circular RNA
circHIPK3 plays a role in diabetic retinopathy by blocking
microRNA 30A function, leading to increased endothelial
proliferation and vascular dysfunction. These data suggest that
the circular RNA may be a potential target for diabetic
proliferative retinopathy.


                                            
The next study identified important new principles of endogenous
chromatin structure that have key implications for epigenetic
therapy. In this study from first author Dr Rosa-Garrido,
corresponding author Dr Vondriska, and colleagues of David Geffen
School of Medicine in UCLA, the authors examined changes in
chromatin configuration in cardiomyocytes isolated from mouse
hearts subjected to transverse aortic constriction or hearts
subjected to Tamoxifen inducible cardiac specific excision of
CTCF, which is a ubiquitous chromatin structural protein.


                                            
There was several important findings from this work. Firstly, the
authors found that depletion of CTTF was sufficient to induce
heart failure in mice and human heart failure patients receiving
LVADs also showed increase CTCF abundance. Pressure overload or
CTCF depletion selectively altered the boundary strength between
topologically associated domains, which are regions of DNA in
which physical interactions occur frequently. The authors showed
that there were changes in the compartmentalization of active
chromatin and inactive chromatin segments, which is a measure of
genomic accessability.


                                            
Heart failure involved decreased stability of chromatin
interactions around disease causing genes. In summary, these
finding provide a high resolution chromatin architectural
resource for cardiac epigenomic investigations and also
demonstrate that global structural remodeling of chromatin
underpins heart failure.


                                            
The final study is the first to provide insights into the fluid
mechanics of transcatheter valve thrombosis. First author Dr
Midha, corresponding author Dr Yoganathan and colleagues from
Georgia Institute of Technology and Emory University in Atlanta
analyzed post-procedural four dimensional volume rendered CT data
of transcatheter aortic valve replacement, or TAVR patients,
enrolled in the Resolve trial, excluding patients on
anticoagulation. Patients were classified as having transcatheter
heart valve thrombosis if there was any evidence of
hypoattenuated leaf thickening. The authors studied the flow
characteristics within the neo sinus which is formed followed
deployment of a transcatheter valve into a native aortic valve.


                                            
The authors found that post deployment valve geometry and final
implant position affected the flow within the neo sinus, which in
turn, may affect the predisposition to thrombus formation. The
impact of geometry and position varied according to the different
valve types. A supra-annular transcatheter heart valve deployment
resulted in a nearly seven fold decrease in stagnation zone size
when compared to an intro-annular deployment. In addition, the in
vitro model indicated that the size of the stagnation zone
increased as cardiac output decreased. In summary, deployed
transcatheter heart valve geometry may have implication on the
occurrence of thrombosis and a supra-annular neo sinus may reduce
thrombosis risk due to reduced flow stasis. While additional
prospective studies are clearly needed, these results may help
identify patients at higher thrombosis risk and aid in the
development of the next generation of devices with reduced
thrombosis risk.


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


                                            
Sudden death in hypertrophic cardiomyopathy has been and still is
a very hot topic in cardiology. Of course it's understandable
given all the high profile deaths that have occurred in young
athletes ascribed to hypertrophic cardiomyopathy and the fact
that these deaths may potentially be preventable with implanted
defibrillators. However, we're so proud to have in this week's
journal, some of the first data on the population-based burden of
sudden death associated with hypertrophic cardiomyopathy. I'm so
happy to have with us the corresponding author of this research
letter, Dr Sumeet Chugh from Cedar Sinai Medical Center, as well
as Dr Mark Link, associate editor from UT Southwestern. Welcome,
gentlemen.


Dr Sumeet
Chugh:           
Thank you.


Dr Mark
Link:                   
Thank you.


Dr Carolyn
Lam:              
Sumeet, you know as I said in the introduction, sudden death in
hypertrophic cardiomyopathy, we've talked about it a lot. There's
been lots published. What makes your data so novel?


Dr Sumeet
Chugh:           
There is indeed a large body of work related to hypertrophic
cardiomyopathy but most of it came from registries. Probably
what's a bit unique about our work is that it was done in one
large, US community over a number of years.


Dr Carolyn
Lam:              
Indeed. So population-based statistics, not just of hypertrophic
cardiomyopathy, but of sudden death related to it, isn't it?


Dr Sumeet
Chugh:           
That's correct, Carolyn.


Dr Carolyn
Lam:              
I think the other thing that we were just actually chatting about
is the fact that it's contemporary. Could you tell us maybe the
period you're looking at and then give us your findings?


Dr
Chugh:                          
Yes. The study was initiated in 2002 and is now in it's 16th
year, so this particular analysis was conducted between the time
period 2002 and 2015. What we do in the process of this
community-based work is that we track prospectively every cardiac
arrest that happens in the community centered around Portland,
Oregon in the USA. The work in performed in the process of doing
a multiple-source ascertainment where we take the help of the
first responders or the ambulance personnel, the hospital
emergency rooms, as well as the police, and the coroner network.
It's a fairly comprehensive way of ascertaining sudden cardiac
arrest.


Dr Carolyn
Lam:              
That is a very unique and valuable data set. Could you summarize
the top line results, because they were rather surprising?


Dr Sumeet
Chugh:           
We are already learning that over time, with more awareness,
education, and modern management of hypertrophic cardiomyopathy,
the risk of sudden cardiac arrest and the overall morbidity from
hypertrophic cardiomyopathy may be on its way down. What this
study is showing is, that actually the risk of sudden cardiac
arrest and the burden of sudden cardiac arrest from hypertrophic
cardiomyopathy in the community may be quite low. Those are the
main findings.


Dr Carolyn
Lam:              
Yeah. In fact, I was just so impressed because first of all, you
excluded the individuals in this population and found that
hypertrophic cardiomyopathy was responsible for 1 in 30 of the
cardiac deaths, but that the incidence of the sudden deaths were
0.2 to 0.3% among these hypertrophic cardiomyopathy patients,
perhaps less than others may have expected.


                                            
Mark could I bring you in on this for a moment? What do you think
are the take home messages for something like this, because in a
young and middle age population, is any rate really too low?


Dr Mark
Link:                   
I think this is great data because it encompasses an entire
population, so it gets us good data on the true incidence of
sudden cardiac death. In the study, if you look at the total
number of patients that either had an ECHO or had an autopsy,
about 5%, a little over 5% of them, had hypertrophic
cardiomyopathy. Roughly 5% of the individuals dying suddenly,
under age 60 are dying secondary to hypertrophic cardiomyopathy.
That's the sort of data that we really didn't have before because
we didn't have such a nice population-based study.


                                            
It was interesting also, they tended to be younger, 10 years
younger than the others dying suddenly, so it was a younger
cohort. They more often had ventricular fibrillation or
ventricular tachycardia than the others dying suddenly. It really
does give us some nice data on the true incidence of sudden death
due to HCM in the community.


Dr Carolyn
Lam:              
What I thought was also valuable was the fact that the diagnosis
of hypertrophic cardiomyopathy was quite often missed prior to
the cardiac arrest and I'm trying to wrap my head around about
what that implies.


Dr Sumeet
Chugh:           
That's a very important point, Carolyn. These findings also give
us the message that our risk classification methodology continues
to need more work. The fact remains that a significant proportion
of patients with hypertrophic cardiomyopathy are also going to be
asymptomatic. Sometimes they just don't come to our attention.


                                            
Another important point, however, that's related to this work is
that there may have been during the course of this time period,
at least a few patients in this community who would have received
an implantable defibrillator and their sudden cardiac arrest
would have been averted, so we're not able to count those
individuals who were already found and managed.


Dr Mark
Link:                   
That's a very important point because if a person is found with
HCM and has risk factors, they would get a implantable
defibrillator. Those individuals would not show up in this
database because they wouldn't die.


Dr Carolyn
Lam:              
Mm-hmm (affirmative)-


                                            
That's a very, very important point. Thank you for highlighting
that. I think it goes back to why these data are so important,
because they are contemporary as well and we really need such
estimates, so congratulations Sumeet and thank you for giving us
these valuable data.


                                            
I'd like to switch tracks a little bit though, and point out this
was a research letter, a big data set, important findings, but
published as a research letter. Should I even say but? Mark could
you comment a little bit about research letters in circulation
versus original articles?


Dr Mark
Link:                   
We increasingly are using research letters in circulation for
original research that drives home a basic single point. If that
basic single point can be made in 1,200 words, we actually like
the research letter format. It's a quick read, people remember
it, it's cited. It is something that authors that we ask to turn
a full length manuscript into a research letter, should be taking
that as a positive sign, because that means that we're interested
in the topic and would like to see it in print.


Dr Carolyn
Lam:              
I completely agree and in fact, Sumeet, if I could ask you to
weigh in. Sometimes it's harder, isn't it, to write a research
letter than to write a full length manuscript? How was your
experience?


Dr Sumeet
Chugh:           
I have to admit that the first responses as you said, where you
feel, "Oh, I've spent a lot of effort in writing this large
paper, and now I have to squeeze it into 1,200 words," but the
second thought for me was, "The fact is that this is a one bullet
message and why not make it shorter and snappier as it is?" I
think I've come around in the appropriate situation to
appreciating this opportunity of writing a research letter.


Dr Mark
Link:                   
when you read the research letters, they're very succinct. I
actually like them. They get the message across quickly and I
think it's a great way to produce science and to show what you've
done.


Dr Carolyn
Lam:              
Yeah. The thing is that we also restrict to a single figure, or a
single table and I cannot tell you how many times I've referred
to that single figure because it usually tells the full story and
it's beautiful summary.


                                            
So, listeners, you've heard about the research letters in
circulation. Please have a look at them. I'm pretty sure that you
will fall in love with the format just like we all have.


                                            
Thank you so much, Sumeet and Mark for joining me today. I'm
afraid our time is up, but I've so enjoyed talking to you. Thank
you, listeners, for following us today. Don't forget to tune in
again next week.