Circulation November 21, 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. This week's journal
features novel results from the NCDR IMPACT Registry that informs
us on risk prediction in patients with congenital heart disease
undergoing cardiac catheterization. We'll be taking a deep dive
into this right after these summaries.


                                               
The first original paper provides pre-clinical data showing that
delayed repolarization may underlie ventricular arrhythmias in
heart failure with preserved ejection fraction or HFpEF. First
author Dr. Cho, co-corresponding authors Dr. Marban, and
Cingolani from Cedars-Sinai Heart Institute and their colleagues,
induced HFpEF in Dahl salt-sensitive rats by feeding them a
high-salt diet from seven weeks of age. They showed that
susceptibility to ventricular arrhythmias was markedly increased
in rats with HFpEF.


                                               
Underlying abnormalities included QTc prolongation, delayed
repolarization from down-regulation of potassium currents, and
multiple re-entry circuits during ventricular arrhythmias. These
findings are consistent with the hypothesis that potassium
current down-regulation may lead to abnormal repolarization in
HFpEF, which in turn predisposes to ventricular arrhythmias and
sudden cardiac death.


                                               
The next paper shows that genetic testing can help to identify
patients with pulmonary veno-occlusive disease who were
misclassified as pulmonary arterial hypertension. Now,
heterozygous mutations in the gene encoding the bone
morphogenetic protein receptor type II or BMPR2 are the commonest
genetic cause of pulmonary arterial hypertension. Whereas
biallelic mutations in the eukaryotic translation initiation
factor 2 alpha kinase 4 gene or EIF2AK4 gene are described in
pulmonary veno-occlusive disease and pulmonary capillary
hemangiomatosis.


                                               
In the current study, first author Dr. Hadinnapola, corresponding
author Dr. Morrell, and colleagues from University of Cambridge
performed whole genome sequencing on the DNA from 864 patients
with pulmonary arterial hypertension, as well as 16 patients with
pulmonary veno-occlusive disease all recruited to the NIHR
BioResource – Rare Diseases study. They found that 1% of patients
with a clinical diagnosis of pulmonary arterial hypertension
actually carry the biallelic EIF2AK4 mutations. Patients who are
diagnosed clinically with pulmonary arterial hypertension, but
who had a transfer coefficient for carbon monoxide of less than
50% predicted and an age of diagnosis of less than 50 years were
much more likely to carry these biallelic EIF2AK4 mutation. In
fact, the diagnostic yield for genetic testing in this group was
53%.


                                               
Radiological assessment alone was unable to distinguish reliably
between these patients and those with idiopathic pulmonary
arterial hypertension. Importantly, these patients with biallelic
EIF2AK4 mutations had a worst prognosis compared to other
patients with pulmonary arterial hypertension. Thus in summary,
younger patients diagnosed with idiopathic pulmonary arterial
hypertension but with a low transfer coefficient for carbon
monoxide, have a high frequency of biallelic EIF2AK4 mutations
and should be reclassified as pulmonary veno-occlusive disease or
pulmonary capillary hemangiomatosis. They have a poor prognosis
and genetic testing can therefore identify these misclassified
patients allowing appropriate management and early referral for
lung transplantation.


                                               
The next study identifies a novel molecular target for the
treatment of pathological cardiac hypertrophy. This target is
SIRT2 [inaudible 00:04:33] poorly characterized member of the
Sirtuin family of proteins, which is a family of class III
NAD-dependent deacetylases that regulate metabolism and
age-related diseases including diabetes and cardiovascular
diseases. In the current study, first authors Dr. Tang and Chen,
corresponding authors Dr. Chen and Liu from the Chinese Academy
of Medical Sciences in Peking Union Medical College used
wild-type and Sirt2 knockout mice, and showed that SIRT2 protein
levels and activity were reduced during pathological cardiac
hypertrophy.


                                               
SIRT2 deficiency promoted aging and angiotensin II induced
pathological cardiac hypertrophy, and blunted metformin-mediated
cardioprotective effects. On the other hand, SIRT2 overexpression
repressed pathological cardiac hypertrophy. The molecular pathway
involved deacetylation of liver kinase B1 at lysine 48 by SIRT2
to activate AMP-activated protein kinase sickling, which
prevented hypertrophy of cardiomyocytes. Thus, SIRT2 is a
potential target for therapeutic interventions in aging and
stress-induced cardiac hypertrophy.


                                               
The next study is the largest comparison of the prognostic value
of coronary artery calcium with functional stress testing in
patients with stable chest pain. In this study from first and
corresponding author Dr. Budoff from Los Angeles Biomedical
Research Institute and colleagues, authors looked at the PROMISE
trial where patients with stable chest pain or dyspnea, and
intermediate pre-test probability for obstructive coronary artery
disease were randomized to functional testing or anatomic
testing.


                                               
Their main finding was that these chest pain populations referred
for testing had a low event rate and both tests had different
strengths. Coronary artery calcium had a high sensitivity for
future cardiovascular events whereas functional testing had a
high specificity. The clinical implications are that a normal
coronary artery calcium score has a very low event rate and
perhaps maybe used to avoid further cardiac testing in a stable
chest pain population. On the other hand, an abnormal functional
test result including information on exercise and symptoms has a
moderate prognostic value.


                                               
Of note, coronary CT angiography provided better prognostic and
discriminatory power than either coronary artery calcium or
functional testing. The implications of these important results
are discussed in an accompanying editorial by Dr. David Newby
from Edinburgh entitled, Can I Have My Cake and Eat It? On that
intriguing note, we've come to the end of today's summaries, now
for our feature discussion.


                                               
For today's feature discussion, we are talking about an
increasingly important population that is pediatric and adult
patients with congenital heart disease undergoing cardiac
catheterization. A little bit out of my usual comfort zone, but
then you see, I'm with two spectacular experts today, Dr. Gerard
Martin from Children's National Health System in Washington DC,
one of the authors of today's feature paper; and Dr. Gerald
Greil, Associate Editor from UT Southwestern. Welcome gentlemen.


Dr. Gerard
Martin:          
Thank you Carolyn.


Dr. Gerald
Greil:               
Thank you Carol.


Dr. Carolyn
Lam:              
Gerard, no that would be Dr. Martin. Enlighten people like me who
don't think about this every day, why the importance of looking
at cardiac catheterization, and adverse outcomes in this
particular population?


Dr. Gerard
Martin:          
Carolyn, that's because of the tremendous advances in medicine,
and particularly medicine that's dealing with children with
congenital heart defects. Cardiac catheterization was once purely
a diagnostic study. Now, it's a less invasive definitive
treatment option for many of our pediatric and adult patients
with congenital heart defects. As you may or may not know,
congenital heart defects are the most common birth defects that
impact nearly one out of every hundred live births.


                                               
As I mentioned, we have these tremendous advances. As a result of
that, there are now over a million children living with
congenital heart defects. In the USA alone, improvements in care
over the past 50 years, there are now more adults than children
living with congenital heart defects.


Dr. Carolyn
Lam:              
Wow. Now, I understand. I mean, cardiac catheterization not just
meeting diagnostic but therapeutic, and such an important patient
population. Tell us about your study?


Dr. Gerard
Martin:          
As we said, cardiac catheterization is now replacing surgery for
some of our defects. For some of the more complex defects,
catheterization is providing treatments that make the surgery
easier. Now in surgery, we've had registries for many years.
These registries provided measurement of survival that allow
comparison of programs, and we didn't have that ability with
cardiac catheterization. The American College of Cardiology
developed the IMPACT Registry. That was to solely provide
measurements of the outcomes of catheterization procedures in the
children and adults with congenital heart disease.


                                               
Now, one aspect of the quality of the program is your rate of
adverse outcomes; but simply measuring the number of adverse
outcomes does not provide enough discrimination to compare
programs. I think you can probably imagine that adverse outcomes
will increase based upon the complexity of the type of patients
you see, or the types of procedures that you might be performing.
What we wanted to do was to create a risk standardization tool
for our population where we can measure variation and performance
between programs. If we can do that, then we can learn from the
best performers to improve all the others.


Dr. Carolyn
Lam:              
That's beautifully put. Could you tell us what you found?


Dr. Gerard
Martin:          
Sure. The IMPACT Registry began on about 2011 and has grown from
50 sites to 111 sites in 2017. That's the majority of the sites
in the United States that perform cardiac catheterization on
children. We have now over 115,000 procedures. What we wanted to
do with this is to look at some of the early procedures that were
included and to see how adverse events were occurring. When we
created the registry though, we used data variables from a
previous research study in Boston called the CHARM.


                                               
They created a tool to risk standardized outcomes during
procedures. They did it by coming up with four categories of
procedures, and some four markers of hemodynamic vulnerability.
We tested their methodology with IMPACT, and it didn't really
performed particularly well. In this study, what we did was to
increase the number of risk categories. We took the nearly 200
types of procedures we do in the cath lab and divided them into
six categories. We also increased the indicators of hemodynamic
vulnerability from four to six.


                                               
Now, what I mean by hemodynamic vulnerability? What is the
patient's oxygen level when they go into the procedure? What is
their blood pressure when they're in the procedure? Do they have
one ventricle, or do they have two ventricles? What is the
resistance in the lung vessels? All these are critically
important. Lastly, we looked at some baseline patient
characteristics. In other words, was age important? Sex, genetic
conditions, or other comorbid conditions like the level of
mechanical support that the patients were on. Then we put all
that into our model to see if we could come up with a risk score.


Dr. Carolyn
Lam:              
Right. The final adjustment model? Which factors that they
include in the end?


Dr. Gerard
Martin:          
We did find that there are lot of adverse events that do occur.
We found major adverse events occurring in about same 7% of our
patients. Most common adverse events were bleeding, or rhythm
disturbances that require some medicine, or cardioversion during
the procedure, or death during the hospitalizations. We did find
that these major events were more common in the youngest patients
or neonates, children under a month of age, or in patients with
genetic disorders, or single ventricle physiology, and also
patients that went to the cath lab with their kidneys not working
very well.


                                               
In the end, we did create a risk adjustment model that included
the type of procedure that was done, the number of hemodynamic
vulnerability indicators, and whether or not the patient had
renal insufficiency, or single ventricle physiology, or
coagulation, and we found really good discrimination. Our
discrimination had a C-stat of 0.76 in the derivation cohort, and
0.75 in the validation cohort. The slope of the curve was
excellent, so we really think we have something now that we can
use as a tool.


Dr. Carolyn
Lam:              
Gerald, you're a pediatric cardiologist. Could you give us your
perspective on how important these results are?


Dr. Gerald
Greil:               
I think it's the largest and the first study, which kinds of give
us a calibration in our field how successful interventions are.
How we can make centers better without finger pointing on
specific centers, and how to advance the field as a whole? From
that perspective, I'm quite excited that the group offered us to
publish this paper in circulation. I was kind of asking a
question to Dr. Martin because obviously, all essentials are
closely monitored. There's obviously data publicly available. Do
you think there's a risk that this way to monitor centers within
the United States or probably worldwide, that it's potentially
preventing innovation or risky procedures?


Dr. Gerard
Martin:          
I think that, that's a good question. I think it's one thing that
whenever we talk about transparency or public reporting, it's an
argument against it. I think that having a model like this,
actually levels the playing field. In other words, centers that
are risk averse who aren't particularly innovative, you'll be
able to look at those centers, see what type of patients they're
doing and look at their adverse events for a low-risk population.
Then, you can also look and see some other centers that are doing
more complicated procedures, higher risk, and you can see what
their adverse event rate is.


                                               
Certainly, this is only talking about the adverse events. This
has to be put together with the outcome of the procedure. In
other words, if you're trying to relieve an obstruction, did you
relieve it? Did you meet the intended goal of the procedure? This
is only half of the story. The other part of it is, did you get
the intended goal of the procedure? When you put the two of them
together, perhaps some of those centers that are risk averse have
lower complications, but maybe their success rate is lower. This
will be able to tell the public everything they know, and they'll
be able to tell their providers what they need to know to get
better.


Dr. Carolyn
Lam:              
I have to agree. Your paper does highlight, I think. Gerard, just
one other question. What do you think our next steps?


Dr. Gerard
Martin:          
The next step is to test the data. We have a new version of
IMPACT that has rolled out, version 2 that has new procedures in
it. Now, we have to test the data and we actually have to look
for variability. Can we see a variation between the programs?
Then, once we see if there's variation, if we see there is best
performers and those performers that could improve, a question
then is how do we take from what the best performers are doing to
try and lift those that need to improve up. That's going to be
the true hard work for this registry.


Dr. Carolyn
Lam:              
Thank you so much for publishing it with us. Thank you so much
audience for listening with us today. Don't forget to tune in
again next week.