Circulation March 6, 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 Doctor
Carolyn Lam, Associate Editor from the National Heart Center and
Duke National University of Singapore. This week's journal
features an international external validation study of the 2014
ESE Guidelines on Sudden Cardiac Death Prevention in Hypertrophic
Cardiomyopathy. A very exciting discussion coming right up after
these summaries.


                                               
The first original paper this week suggests that proteomics, a
tool of precision medicine may prove useful in improving the
safety and efficiency of drug development. First author, Doctor
Williams, Corresponding Author, Doctor Ganz, from the Zuckerberg
San Francisco General Hospital retrospectively applied large
scale proteomics to blood samples from Illuminate, the trial of
Torcetrapib, a cholesterol estrotransfer protein inhibitor, which
raised HDL and lowered LDL cholesterol. Recall that this trial
was terminated due to increases in cardiovascular events and
mortality.


                                               
In the current study, the authors found that plasma
concentrations of 200 proteins changed significantly with
Torcetrapib. Their pathway analysis revealed unexpected and
widespread changes in immune and inflammatory functions, as well
as changes in aldosterone function and glycemic control. A
previously validated nine protein risk score was similar in the
two treatment arms at baseline, but higher in participants with
subsequent events. At three months, the absolute nine protein
derived risk increased in the Torcetrapib plus Atorvastatin arm
compared to the Atorvastatin only arm. Thus, this protein-based
risk score predicted harm from Torcetrapib within just three
months. A protein-based risk assessment embedded within a large
proteomic survey may prove to be useful in the evaluation of
therapies to prevent harm to patients. This is discussed in an
accompanying editorial entitled "Harnessing the Power of
Proteomics to Assess Drug Safety and Guide Clinical Trials" by
Doctor Maggie Lam and Ying Ge.


                                               
The next study suggests that personalized monitoring of heart
transplant outcomes may be achieved by profiling the genetic and
phenotypic markers of the CD16-dependent natural killer cell
activation pathway. First and corresponding author Dr. Paul from
Vascular Research center in Marseilles in France and his
colleagues collected blood samples from 103 patients undergoing
routine coronary angiography for cardiac allograph vasculopathy
diagnosis, a median of five years since their heart
transplantation. They used a non-invasive natural killer
cellular-humoral activation test to evaluate the association
between genetic and phenotypic markers of the CD16 dependent
natural killer cell activation pathway. They showed that the
Fc-gamma receptor IIIAVV polymorphic variant, which encodes the
highly responsive CD16-Fc receptor, was an independent baseline
predictor of cardiac allograph vasculopathy, and may be useful
for stratifying patients at higher risk of rejection. The
implications of these findings also include the fact that
individualized natural killer cell targeted therapies may limit
vascular damage in responsive patients.


                                               
The next study suggests that estimation of polygenic atrial
fibrillation risk is feasible, and together with clinical risk
factor burden, can explain lifetime risk of atrial fibrillation.
Co-first authors Dr. Weng and Preis, corresponding author Dr.
Lubitz from Massachusetts General Hospital, and colleagues
estimated the lifetime risk of atrial fibrillation in individuals
from the community-based Framingham Heart Study. Polygenic risk
for atrial fibrillation was derived using a score of
approximately 1000 atrial fibrillation-associated SNPs. Clinical
risk factor burden was calculated for each individual using a
validated risk score for incident atrial fibrillation comprised
of height, weight, systolic and diastolic blood pressure, current
smoking, anti-hypertensive medication use, diabetes, history of
myocardial infarction, and history of heart failure.


                                               
They found that the lifetime risk of atrial fibrillation after
age 55 years was 37 percent was substantially influenced by both
polygenic and clinical risk factor burden. Among individuals free
of atrial fibrillation at the age of 55 years, those in the low
polygenic and clinical risk tertiles, had a lifetime risk of 22
percent, whereas those in the high risk tertiles had a risk of 48
percent. Atrial fibrillation developed at an older age among
individuals with a favorable clinical risk profile regardless of
genetic predisposition. Nevertheless, the lifetime risk of atrial
fibrillation in individuals with high genetic predisposition was
substantial, even when the clinical risk factor burden was low.
Thus, individualized projections of lifetime risk of atrial
fibrillation may be refined by accounting for both genetic
predisposition and clinical risk factor burden.


                                               
The final study tells us that in contrast to previous
perceptions, Takotsubo cardiomyopathy has long-lasting clinical
consequences. First and corresponding author Dr. Skally from
University of Aberdeen in the UK and their colleagues did an
observational case controlled study of 37 patients with prior
Takotsubo cardiomyopathy and 37 age, sex, and co-morbidity
matched controls. Although Takotsubo cardiomyopathy occurred 20
months before the study, the majority of patients had persisting
symptoms compatible with heart failure and cardiac limitation on
exercise testing. Despite a normal left ventricular ejection
fraction in serum biomarkers, patients with prior Takotsubo
cardiomyopathy had impaired cardiac deformation indices on echo
cardiography, increased native T1 mapping values on cardio
magnetic residence imaging and impaired cardiac energetic status
on p31 spectroscopy. Taken together, these findings demonstrate
that after Takotsubo cardiomyopathy, patients appear to develop a
persistent long-term heart failure phenotype.


                                               
Well that wraps it up for our summaries. Now for our featured
discussion.


                                               
Sudden cardiac death prevention and hypertrophic cardiomyopathy.
Always such an important topic. I'm so pleased to have with us
the author from our featured paper this week, Dr. Perry Elliot
from University College London, nd our associate editor, Dr. Mark
Link from UT Southwestern who also wrote a beautiful accompanying
editorial with Tera Lynn Ho. So welcome both of you. Perry, I
think to set us up, I'd really love if you could tell us a little
bit more about the 2014 ESE guidelines for sudden cardiac death
prevention and hypertrophic cardiomyopathy. And particularly
pointing out how they may differ from the 2011 ACC AHA guidelines
please.


Dr Perry
Elliot:                  
So, the 2014 guideline on sudden death prevention HCM, the aim of
that guideline was to try to quantify the risk of sudden cardiac
death. As you pointed out, sudden death is a significant
complication of hypertrophic cardiomyopathy and one which we all
as clinicians spend a lot of time trying to determine. If we look
back over at, I don't know, a period of twenty, thirty years the
approach we've developed is based upon the recognition of a
number of clinical features of the disease that we know associate
with a higher risk of sudden death. So things such as, you know,
unexplained syncope or severity of hypertrophy. And it was that
model of sort of taking those so called major risk factors which
form the basis of the 2011 US guidelines and the essential model
was the more of those things you have, the greater is your risk,
and I suppose the  higher indication for an ICD.


                                               
One of the problems with that approach was that it's not
quantitative so you know, you could say, "Okay. Well I think
you're at higher risk, but I can't say how much that risk is."
And another problem with that way of doing things is when you
start to think about some of the individual risk factors, it
doesn't make a great deal of sense clinically.


                                               
And I suppose a good example of that is wall thickness. You know
we have this magical number of 30 millimeters, above which we say
you're at risk, but of course are we really saying that if your
wall thickness is 29 millimeters you're at low risk? We know it
doesn't really work that way in biology. So when we drew up the
2014 guideline we wanted to say, "Okay let's develop a model in
exactly the same way that we do with atrial fibrillation or
primary prevention in coronary disease so that we can say to the
patient sitting in front of us, 'Based on your clinical
assessment we think you've got a one, five, ten percent risk of
something bad happening to you in the next five years.'" And then
we can use that information to inform our decision about ICD
implantation.


                                               
The model itself is not so revolutionary. I mean, it uses a lot
of the conventional risk factors such as wall thickness, such as
non-sustained VT on Holter monitoring, but what it did introduce
was the factor of age, because we know that the age of the
patient certainly determines their risk. We brought in [inaudible
00:10:12] obstruction because we've now got reasonable evidence
showing that if you've got a big gradient, that certainly
modulates your risk. And also probably for the first time, I
suppose, left atrial size, which was one of those missing things
I think in previous assessments. You know, it's a fantastic
surrogate for restrictive physiology and certainly when we added
it to the model it improved the predictive power of that model.


                                               
So I suppose in summary what we've done is to produce a tool
which allows you to estimate risk and then use that to help you
decide on whether an individual needs a defibrillator in the
clinic.


Dr Carolyn
Lam:               
You know Perry I believe you led those guidelines and I just want
to congratulate you as well as that was such a beautiful
explanation of what was going on behind those. Yup, but the proof
is in the pudding isn't it? But you're providing that proof in
today's paper. Tell us about it. So it's an external validation,
a large international multi-centers study to actually validate
these 2014 guidelines.


Dr Perry
Elliot:                  
That's right. I mean, I think when we generate these kind of
models it's really important to test those models in different
settings. The original model was based upon a relatively small
number of European centers and I think what this paper does is it
brings insights into different geographies and different health
care systems. So we have participating centers from North America
from the Middle East from the Far East and the idea here is to
get as diverse a population as we can and just see if the model
performs in the same way. And you know in a study just short of
4000 people, I think that we've shown that the model does indeed
seem to behave in the same way. In fact, the numbers were
remarkably similar. You know the ability of this model to
discriminate between high and low risk patients was almost
exactly the same as in the original paper, which I think gives us
a level of reassurance that this model, this tool that we've
developed, can be used in different health care settings.


Dr Carolyn
Lam:               
Mark. I really enjoyed your editorial. I love the way that you
started out with a case that really shows why this is so
important. And I also love that you discuss some other studies
that tried to validate the 2014 ESE guidelines as well. Could you
just give us some of your thoughts there.


Dr Mark
Link:                    
Yeah. I first want to congratulate Perry and his fellow authors
for this paper. I think it was a very nice paper. I was a
champion of this paper from the time it got sent into
circulation. And, you know, the big change in the 2014 European
guidelines compared to the American guidelines is really the
linear risk of age, wall thickness, and I'll put tract gradient.
And as Perry says, I agree, it's not a simple you have it or you
don't, it's a linear risk and I applaud them for including that
in their risk factor stratifier. And if you look at the current
paper, I mean it was very good at picking out high risk patients.
So if you have greater than a four percent, six percent risk over
five years, you did. And so for picking out the high risk
patients it was very good. And for picking out the medium risk
patients, it didn't function as well. It was best for separating
out the high risk and the low risk population.


                                               
And I will say, based on this paper, I've started using the
European risk stratifier in my clinical practice. So I do want to
applaud them, you know, for the risk stratifier tool and this
paper. But I do want to say, and I'm sure Perry will agree, that
we're not there yet. We need better tools, because not only in
this data set but in other data sets, because more of these
individuals reside in the low risk population, more of the sudden
deaths are in that population. And we need better tools. And over
time they will come. You know, they may be MRI tools. They may be
scar tools. They may be other tools that we aren't even aware of
that are coming on the horizon, but we do need better tools as we
move forward to identify those at risk for sudden death in
hypertrophic cardiomyopathy.


Dr Perry
Elliot:                  
Yeah. No. I agree. I mean I think what I would say is if you sort
of take a step back and look at the overall perspective in this
paper, despite the fact that, you know, we've got nearly 4000
people and they're followed in different health care settings,
the overall sudden death rate in hypertrophic cardiomyopathy
pretty low. You know, so that's good for patients 'cause I think
it shows that at least in managed populations, the risk of sudden
death which is real and we've got to assess it, but I think it's
really important to get that message over to patients that for
most people with HCM they're at low risk. It is of course the
challenge because when you're dealing with rare events, it's
really hard to predict them. And this model is far from perfect.
I would argue it's probably the best we've got for the moment,
but you know, it's not that bad. It's not that bad.


                                               
I mean agree with you absolutely Mark, 'cause you know, either
end it performs pretty well. In the middle there it's not as
predictive, although what it tends to do is overpredict, rather
than underpredict. So you know, I think if you use this model in
your every day practice just the greatest risk is that you'd end
up putting in probably more ICDs then you really need to rather
than missing a lot of patients. You know, we really want to
prevent every sudden death if we possibly can, but that's always
going to be really hard I think and I think the fight goes on. We
got to look for new risk predictors. It may be that we can
interchange some of these predictors. They might be easier to
assess in some practices, but I'm not a born optimist, but I
really think it's amazing just how well in such a complex
heterogeneous disease that this relatively simple assessment
works. You know?


Dr Mark
Link:                    
Going forward, what do you think the future of HCM [inaudible
00:15:47] stratification will include? We've got the risk
stratifiers in your calculator ready. And more specifically where
do you think gadolinium enhancement will play a role in the
future? So MRI findings of scar or gadolinium enhancement.


Dr Perry
Elliot:                  
The base we have at the moment show that the more scar you have,
the greater risk of sudden death. It sort of makes sense, doesn't
it? It's part of that substrate for ventricular arrhythmia. My
own reading of it just so far is that I'm not sure what it adds
to the existing way of doing things. I mean I think this is true
of any biomarker, you know. I've got a new biomarker, what does
it tell me that I don't already know? And with scar, we know the
greater amount of scar, it often tracks with wall thickness.
You're likely to have a thicker heart, you're more likely to have
non-sustained VT. But I'm openminded on that front. The beauty
about this model, for me, is that it's a tool to into which you
can plug other things and you know, if we can get big enough data
sets and we can use gads and the amount of scar and put that into
the model and if it improves the performance of the model that's
great. Those studies are underway at the moment and I think we
eagerly wait the results of those studies.


                                               
For me, one of the missing things is the genetics. This is a
heterogeneous disease with quite a complex genetic architecture,
and despite the fact that you know it's 20, 30 years now since we
identified the first gene, we haven't really factored that in to
our risk models and I think that for me is one of the big
challenges and opportunities over the coming years is to put
together really large international data sets so that we can
answer once and for all whether your mutation determines your
prognosis.


Dr Mark
Link:                    
Yeah. I agree with the genetics also I think getting more
information on that. And it’s been 30 years it still is not
helping us prognosticate the risk of sudden death, but it should.
I mean it really should. And I do think hopefully we will find
other tools also as time goes on because it really is imprecise
and it's very difficult when you're sitting there in front of ...
You know, I just had a 20 year old yesterday come in with his
family and he's got a three centimeter septum and he's got 12
percent scar and he's saying, "Gee what would you do and what
would you do if I were your son?" And it's easy when you're
looking at it in the aggregate. It's much more difficult when
you're sitting there one on one with a patient in front of you.


Dr Perry
Elliot:                  
Of course. Of course. And I think another factor I think which is
changing the dynamic of that kind of discussion is the evolution
of ICD technology. You know, I think when you're dealing with
young people the fear is long-term complications with leads isn't
it? And I think with the advent of the SICD I sense it's already
tipping the balance into perhaps a slightly more liberal approach
to ICD implantation exactly in the kind of scenario you've just
described Mark, you know you've got guy who's 20. He's got a
really severe hypertrophy. Well you know, if you and mess ICD you
know your threshold for implantation might be a bit lower.


Dr Mark
Link:                    
Yeah and in fact, after a two hour discussion that's what we
decided on is that subcu ICD was the right thing for him. And
everyone's very happy with that choice.


Dr Perry
Elliot:                  
Yep. I think it also raises another thing which I often think
about is that as medics we're also probably not good at
considering what acceptable risk actually is. You know? We
develop models in different settings and hyeprtrophic
cardiomyopathy, coronary disease, heart failure, and actually if
you go back and critically look at the thresholds that are used
to put in defibrillators, the absolute risks vary enormously. So
you know, here in [inaudible 00:19:02] we're talking about an
approximate annual risk of sudden death of about one percent per
annum is sufficient to put in an ICD, but in long-QT world it's
quite a different threshold that's used and of course that's
because there is no defined number. You know the number's we used
in the ESE model of greater than six percent you should have an
ICD, well yeah that's the consensus number, there's nothing
magical about it. There's nothing biological about it. And I
think we've probably had greater debates at what acceptable risks
really are.


Dr Mark
Link:                    
And that's become a big shared decision now in the States and
actually everywhere. It's become a big word because it sued to be
that the physicians would decide on who gets an ICD and who
doesn't. And it's no longer that way it's a discussion with the
patient, with the family. How much risk are they willing to take,
both with an ICD and without an ICD, because there are issues
with ICD, even though I'm a big fan. There are issues and
especially with transvenous ICDs, but also with subcutaneous
ICDs.


Dr Perry
Elliot:                  
Absolutely. Absolutely.


Dr Mark
Link:                    
You know, it's a different world now than it was 15 20 years ago.


Dr Carolyn
Lam:               
Perry and Mark, this has been one of the most wonderful
conversations I've had on these podcasts. I just can't thank you
enough. I'm sure all our listeners are thanking you too. You've
been listening to Circulation on the Run. You must tune in again
next week for more beautiful conversations.