Circulation April 16, 2019 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 in Duke
National University of Singapore.


Dr Greg
Hundley:            
And I'm Greg Hundley, also associate editor of Circulation and
director of the Poly Heart Center at BCU Health in Richmond.
Carolyn, we've got a really exciting interview to follow our
coffee chat and it's evaluating individuals with low complexity
congenital heart disease. We often think of those with high
complexity congenital heart disease and looking at their
cardiovascular events. We're going to hear a little bit about low
complexity congenital heart disease.


                                               
Now you've got a paper you wanted to talk about first.


Dr Carolyn
Lam:               
Absolutely. You've got to hang on for that because I'm going to
delve into chromatin architecture in heart failure, and it's in
this paper from corresponding author Dr Foo from Genome Institute
of Singapore.


                                               
So, as background, the human genome actually folds in 3D to form
thousands of chromatin loops within the nucleus encasing the
genes and assists regulatory elements for accurate gene
expression control. Now, these physical tethers of loops are
anchored by the DNA binding protein CTCF, also known as the
weaver of the genome and the cohesion ring complex. Now, the role
of CTC in binding and changes in chromatin structure in heart
failure are not well understood. Well, until today's paper.


                                               
What the author said is they undertook an independent analysis of
chromatin organization with mouse pressure overload model of
myocardial stress or transverse aortic constriction, and a
cardiomyocyte specific knockout of CTCF. So, interestingly, they
found that the cardiac chromatin architectural in adult
terminally differentiated cardiomyocytes was unchanged in
pressure overload from transverse aortic constriction. Now this
was completely unlike the CTCF knockout model where they verified
that there was generation of vast genome-wide loss of genomic
insulation and near complete abolition of the CTCF chromatin
loops.


                                               
Instead of chromatin rewiring on the scale of that knockout, the
myocardial stress response appeared to proceed through enhancer
H3K27 acetylation epigenetic changes and gene network
co-regulation driven largely by fixed cardiac 3D chromatin
architecture. In other words, a stable chromatin architecture
really set the stage for accurate enhancer promoter interactions
required for basal gene expression control and induction of the
classical myocardial stress gene response.


Dr Greg
Hundley:            
So Carolyn, are there therapeutic implications here for this?


Dr Carolyn
Lam:               
Now of course, that was preclinical work, but it really opens the
door to consider these epigenetic regulators that control disease
expression changes and interacting gene sets in heart as
potential future targets for novel heart failure therapy.


Dr Greg
Hundley:            
Very interesting. So, I'm going to review and switch gears a
little bit and focus on diabetic cardiomyopathy and mitochondria
associated endoplasmic reticulin membranes. And this paper is
from Shengnan Wu from the Center for Molecular and Translational
Medicine at Georgia State University here in the US in Atlanta,
Georgia. So as we all know, mitochondria are essential for
cellular energy production, but when they're damaged, they become
a major source of reactive oxygen species and pro-apoptotic
factors. In particular, increasing evidence suggests that
mitochondrial dysfunction is a central event in diabetic
cardiomyopathy.


                                               
Well, the mitochondria and the endoplasmic reticulum are key
players that regulate many cellular functions and their
structural and functional interactions are essential for cellular
homeostasis. The contact points, however, through which the
endoplasmic reticulum communicates with mitochondria, they're
known as mitochondria associated endoplasmic reticulum membranes,
or MAMS. Importantly, MAMS play a pivotal role in calcium
signaling, lipid transport, energy metabolism and cell survival,
and they've been implicated in a variety of diseases, including
Alzheimer's Disease, cancer, lysosomal storage diseases,
diabetes, obesity induced mitochondrial dysfunction and other
metabolic disorders.


                                               
But the role of these MAMS in the initiation and progression of
Diabetic Cardiomyopathy is really unknown. So now, FUNDC1 is a
highly conserved protein that's exclusively localized to the
mitochondria. And this group had previously demonstrated that
FUNDC1 was essential for maintaining the structure of MAMS and
ensuring appropriate calcium transfer from the endoplasmic
reticulum to the mitochondria normal hearts. Moreover, cardiac
specific deletion of FUNDC1 induced cardiac dysfunction by
inhibiting MAM formation.


Dr Carolyn
Lam:               
Interesting. So that was their prior work? What did the current
study show?


Dr Greg
Hundley:            
Right, so what the investigator showed in this study is that high
glucose driven inactivation of AMP-activated protein kinase
increased FUNDC1 stability, but resulted in aberrant MAM
formation, impaired mitochondrial calcium increase, mitochondria
dysfunction and then cardiac dysfunction. And additionally, AMP-K
activation reverses Diabetic Cardiomyopathy by suppressing high
glucose induced MAM formation, mitochondrial calcium increase and
mitochondrial dysfunction.


                                               
And interestingly, Metformin, an AMP-K activator, used
exclusively for Type 2 Diabetes, might be effective in treating
Diabetic Cardiomyopathy in individuals with Type 1 Diabetes. So a
very interesting mechanistic study providing some information of
how MAMS, mitochondrial function and endoplasmic reticulum could
be important in understanding how to prevent Diabetic
Cardiomyopathy.


Dr Carolyn
Lam:               
Indeed. And you know, that last note that you made on Type 1
Diabetes, also links very well with the next paper that I chose.
Which really asks the question, in Type 1 Diabetes, what are the
relative prognostic importance and optimal levels of risk factors
for mortality and cardiovascular outcomes? And this comes from Dr
Rawshani and colleagues from the Swedish National Diabetes
register who studied more than 32,600 patients with Type 1
Diabetes in their national observational cohort study from the
Swedish National Diabetes register, with a mean follow-up of 10.4
years and a mean duration of diabetes of 17.9 years.


                                               
They found that the most important predictors for outcomes were
HP-A1C, albuminuria, duration of diabetes, systolic blood
pressure and low-density lipoprotein cholesterol, or LDL
cholesterol. Now, the lower levels of HP-A1C, systolic blood
pressure and LDL cholesterol than contemporary target levels were
associated with lower risk for outcomes. Albuminuria was
associated with a two to four times greater risk of
cardiovascular disease and death. And each millimole increase of
LDL cholesterol was associated with 35 to 50% higher risk for
outcomes.


Dr Greg
Hundley:            
Boy, Carolyn, those are interesting results. So, what do we take
away from this in clinical management of patients?


Dr Carolyn
Lam:               
The take home message is that in patients with Type 1 Diabetes,
the strongest predictors for mortality and cardiovascular
disease, with the exception of age, were mostly conventional and
modifiable cardio-metabolic risk factors. And this in turn
suggests that increased clinical focus on these risk factors,
particularly in primary prevention, may result in the largest
relative risk reduction for mortality and cardiovascular disease,
even in Type 1 Diabetes. So, future clinical trials may be
designed to test these findings.


Dr Greg
Hundley:            
Very good. Well, Carolyn, my next paper, I'm going to talk about
five year outcomes after off-pump versus on-pump coronary artery
bypass grafting in those over the age of 75 years. And this paper
comes from Anno Diegeler from Bad Neustadt in Germany. From June
of 2008 to September of 2011, they evaluated a total of 2,539
patients that were 75 years or older, who had been randomly
assigned to undergo off-pump or on-pump coronary artery bypass
grafting across 12 centers in Germany.


                                               
And the primary outcome was all cause mortality at five years,
and the secondary outcome included a composite of death,
myocardial infarction and repeat revascularization. What did they
show in this study? Well, after a median follow up of five years,
the hazard ratio for off-pump versus on-pump coronary artery
bypass grafting was 1.03, confidence interval 0.81 to 1.19, no
difference. The composite outcome of death, myocardial infarction
and repeat revascularization, the same. Hazard ratio 1.03,
confidence interval 0.89 to 1.18, P-value 0.7.


                                               
So, first take-home message, no difference if you had your
surgery off-pump or on-pump, if you're over the age of 75. Now,
another outcome related to incomplete revascularization. And what
was striking I this study is whether you underwent on-pump or
off-pump bypass, if you were incompletely revascularized, that
was associated with both the primary as well as the secondary
outcomes. So, in elderly patients, in summary, greater than or
equal to 75 years, the five year survival rates as well as the
combined outcome of death, MI and repeat revascularization, was
similar for on-pump versus off-pump CABG. And incomplete
revascularization was associated with a lower five year survival
rate, irrespective of the type of surgery that was performed.


Dr Carolyn
Lam:               
Interesting. Beautifully summarized, Greg. Thank you.


Dr Greg
Hundley:            
Absolutely. And let's head on to that featured article.


                                               
Well, welcome everyone to the second half of our program. We are
very excited today to have Dr James Priest, from Stanford
University School of Medicine. And also our associate editor
Gerald Greil from University of Texas Southwestern School of
Medicine in Dallas. And we're going to be discussing the article,
Substantial Cardiovascular Morbidity in Adults with Lower
Complexity Cardiovascular Disease.


                                               
So, James, first could you tell us a little bit about what
constitutes low complexity congenital heart disease? And then a
little bit about your study population, your design, and the
results that you found with your study?


Dr James
Priest:               
So, low complexity congenital heart disease really derives from
definitions of congenital heart disease in adults that are grown
up and have different complexity of lesions. And so high
complexity congenital heart disease, you see things that, as
people may remember, adult cardiologists may remember from their
training. People remember from medical school, things like single
ventricle disease, hypoplastic left heart, tetralogy of fallot,
transposition of the great arteries. But, non-complex, so our low
complexity disease, really constitutes a relatively simple
malformation. Things like atrial septal defects, ventricular
septal defects, patent ductus arteriosus. Things that are
treatable with a single surgery.


                                               
You close the hole, you ligate the vessels, you dilate the valve,
and the patient is affectively cured. So relatively low
complexity diseases that can be treated with typically, a single
surgery or minimal interventions to restore completely, or
essentially normal, cardiovascular physiology.


                                               
So, the study was based upon a very large you know, volunteer
data set, the UK Biobank. It comes from the United Kingdom where
500 thousand individuals enrolled, and from those individuals
there is genetic information, medical histories dating back to
the 1990s, self-reported history. A variety of functional and
neuropsychiatric measures. And if you get a group of 500 thousand
individuals from anywhere, there's going to be some congenital
heart disease in there. And so, we looked to see what types of
congenital heart disease were in there. And in fact, there was
lower complexity individuals.


                                               
And because I spent some time on the research side of things with
my adult colleagues, the first thing we looked at were from the
common adult cardiovascular outcomes, things people write about
in Circulation all the time. Coronary artery disease, atrial
fibrillation, heart failure. We know these things are problems in
adults with complex cardiovascular disease, but nobody had really
looked for the most part in adults with low complexity or
non-complex disease. And we were surprised to see such high event
rates for these common adult cardiovascular conditions.


Dr Greg
Hundley:            
So, what type of events did you appreciate in the population in
follow up?


Dr James Priest:
              
So, we really appreciated about a two-fold rate of let's say,
acute coronary syndrome relative to the general population. Up to
almost 13 fold risk of atrial fibrillation and heart failure,
relative to the general population. So, really substantial and
very impactful event rates.


Dr Greg
Hundley:            
Very good. And so, just a couple points of clarification. Do you
think that the events you observed, were they related to the
congenital heart disease, per se? Or could it have been a result
from the surgical procedure to treat that heart disease?


Dr James
Priest:               
So, that's a great question. I think, in some ways, that's the
fundamental question that the paper leads to. So, we thought of
it in two different ways. You know, one, were these events, and
they're perioperative events, for individuals receiving some type
of care for their congenital heart disease, during their
adulthood? And we performed a sensitivity analysis where we
basically looked at those events and then looked for events
occurring within a year of adult interventions. And we saw no
difference in those event rates. So, they weren't perioperative
or postoperative events in adults receiving adult congenital
heart disease care.


                                               
The second part of the question is really more of an existential
question in some ways. You know, is there some fundamental
relationship between the care these people received as children?
Or the genetic basis of congenital heart disease in the first
place that is somehow put people at risk long term for adult
cardiovascular disease, acquired adult cardiovascular disease?
And I think there's indeed a lot of different ways to try and get
at that question and explore that more, which we're currently
working on.


Dr Greg
Hundley:            
So, Gerald, I wanted to turn over to you now and, in your
practice that encompasses those that are young adults that have
this low complexity congenital heart disease, how do you manage
them now? And how might the results of this study suggest,
potentially, a different management strategy?


Dr Gerald
Greil:                
Usually these patients, they're kind of thought to be cured or
only needed minimal follow up in the past. So, if you take a
patient with a VSD, rarely during childhood, young adult or even
kind of in 20s and 30s, you have any major difficulties. And as a
pediatric cardiologist, you rarely experience any major follow up
problems with these patients. I think, particularly in the US,
and I work actually for more than 10 years in the UK, the problem
in the US is how can you organize follow up in these patients?


                                               
There're insurance issues, there're issues about moving into
different areas, and since these patients were kind of labeled as
being healthy and close to normal, they were lost for follow up,
particularly in the US. I think this study raises some concerns,
we should probably be more careful and cautious and follow these
patients up kind of in a lifelong session. And take care of them.
This is definitely something, which is a new finding, and what
the cause is, how we are following up, that's the question. I
guess it could be a good question for future studies.


Dr Greg
Hundley:            
You mentioned future studies. Specifically, what type of future
studies do you think we need to perform next? This shows us that
the events are occurring, are we ready yet for randomized trials
to perform prevention? Do we need studies that have more frequent
observation? What are your thoughts there? And I'll get your
answer and then we'll come back to James and get his thoughts on
the same question.


Dr Gerald
Greil:                
Yeah, I think the major thing is we need close follow up of these
patients. And it will be a combined effort between pediatric and
specialized adult cardiologists, with a special interest in
patients with congenital heart disease. Once again, coming back
to it, a closer follow up is a little bit dependent on the
medical system, which you have. If you take Canada and the UK, it
may be easier in these patients are under close follow up. And
this allows large multicenter studies, large data bases like UK
Bio Bank are kind of exemplary. And we should try to get
something similar within the US or in other countries.


                                               
I think that's the lesson what we take from that, we need larger
data bases, probably more granular than what we have right now. I
mean, James probably can comment in a second about the
shortcomings and what can be done better in the UK Bio Bank to
allow more detailed conclusions than we have currently from his
study.


Dr Greg
Hundley:            
James?


Dr James
Priest:               
I would agree with that. I think as a person who does not,
clinically speaking, take care of adults with congenital heart
disease, my colleagues and I, or I have the impression from my
colleagues that for most of the time, in most of these patients
in the Unites States adults who had VSD or ASD repair as a child,
they were essentially said, oh, you're cured. And they perhaps
had some follow up during childhood, but then were otherwise
discharged to live the rest of their lives.


                                               
And so, in many cases I'd say the first step before performing
any studies is to simply identify who these patients are, and
figure out you know, what their risk factors otherwise for
cardiovascular disease might be. Now, that being said, I think
that was one of the powerful things about the UK Bio Bank study
is that there's a large population in which all these traditional
cardiovascular risk factors you know, obesity, lipid levels,
hypertension, smoking status, all these things were uniformly
measured in both the individuals with congenital heart disease,
the adults with congenital heart disease. And of course the
control population.


                                               
And so that allowed us to make some estimates about what
proportion of disease was attributable to these traditional
cardiovascular risk factors. And what was attributable to other
factors related, potentially, to the congenital heart disease.
But all those things being said, I think the first questions that
I often to tend to receive about these studies from the pediatric
cardiologists and the adult congenital heart disease doctors,
reflects the sorts of data sets that we're used to looking at.


                                               
Well, what sort of an intervention did this person have? Did they
have a ventriculostomy? When did they receive their diagnosis and
their repair? Details of the surgical care and the perioperative
of course, are not available in this data set because it's not a
particularly pediatric cardiology focused data set. It's a broad
population based data set. And so the relationship specifically
the details of their perioperative care and diagnosis are not
able to be attained. And so we'll need larger data sets that
include that information to fully start to develop those sorts of
relationships over time.


Dr Greg
Hundley:            
So, we want to thank our lead author, Dr James Priest from
Stanford University School of Medicine, and our associate editor,
Gerald Greil from the University of Texas Southwestern Medical
School in Dallas. And reviewing this very interesting article on
lower complexity cardiovascular disease and its association with
an increased risk of cardiovascular events. And thank you both so
much for clarifying. It sounds like an opportunity to collect
more data through registries, et cetera, that we may need to
expand around the world.


                                               
Thank you everyone for listening to Circulation on the Run.
Remember that's your back stage pass to our journal. And we'll
see you next week.