Circulation December 4, 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 Dr Carolyn
Lam, Associate Editor from the National Heart Center and Duke
National University of Singapore.


                                               
Our featured paper this week reports the five-year clinical
outcomes and valve durability in the largest available cohort to
date of consecutive high-risk patients undergoing transcatheter
aortic valve replacement. You must listen up for this discussion,
coming right up after these summaries.


                                               
The first original paper describes a personalized risk assessment
platform that promotes the implementation of precision medicine
by helping us with the evaluation of a genomic variant of
uncertain significance. A genomic variant of uncertain
significance is a rare or novel variant for which disease
pathogenicity has not been conclusively demonstrated or excluded
and thus cannot be definitively annotated. These variants
therefore pose critical challenges to the clinical interpretation
and risk assessment. New methods are therefore urgently needed to
better characterize their pathogenicity.


                                               
Co-first authors, Dr Ma, Zhang, and Itzhaki, corresponding author
Dr Wu from Stanford University School of Medicine and colleagues
recruited a healthy, asymptomatic individual lacking cardiac
disease clinical history and carrying hypertrophic cardiomyopathy
associated genetic variant in the sarcomeric gene, MYL3, which
has been reported by ClinVar database to be likely pathogenic.


                                               
Human-induced pluripotent stem cells or IPSCs were derived from
the heterozygous carrier, and their genome was edited using
CRISPR/Cas9 genome editing to generate karyo-specific IPSCs.
Extensive essays, including measurements of gene expression,
sarcomere structure, cell size, contractility, action potentials,
and calcium handling were performed on the isogenic IPSC-derived
cardiomyocytes, and together, the platform was shown to elucidate
both benign and pathogenic hypertrophic cardiomyopathy-functional
phenotypes.


                                               
Thus, this paper demonstrates for the first time the unique
potential of combining IPSC-based disease modeling and
CRISPR/Cas9 genome editing technology as a personalized risk
assessment platform for determining the pathogenicity of a
variant of unknown significance for hypertrophic cardiomyopathy
in a patient-specific manner.


                                               
Transcatheter aortic valve replacement is increasingly being used
for the treatment of severe aortic valve stenosis in patients at
intermediate risk for surgical aortic valve replacement. The next
paper provides real world data comparing indications and clinical
outcomes of patients at intermediate surgical risk undergoing
isolated transcatheter vs. surgical aortic valve replacement.


                                               
Co-first and corresponding others, Dr Werner and Zahn from
Clinical Ludwigshafen in Germany compared clinical
characteristics and outcomes of more than 7,600 patients with
intermediate surgical risk who underwent isolated transcatheter
or conventional surgical aortic valve replacement within the
prospective all-comers, German aortic valve registry between 2012
and 2014.


                                               
Multi-variable analyses reveal that factors that were associated
with performing transcatheter instead of surgical aortic valve
replacement included advanced age, coronary artery disease, New
York Heart Association class three or four, pulmonary
hypertension, prior cardiac decompensation, and elective
procedure, arterial occlusive disease, no diabetes mellitus, and
a smaller aortic valve area.


                                               
Unadjusted in-hospital mortality rates were equal for
transcatheter and surgical aortic valve replacement, whereas
unadjusted one-year mortality was significantly higher in
patients with transcatheter aortic valve replacement. After
propensity score matching, the difference in one-year mortality
was no longer significant. Thus, this large registry analysis
suggests that both transcatheter and surgical aortic valve
replacement are reasonable treatment options in a real world
population with aortic stenosis and intermediate surgical risk.


                                               
The next paper demonstrates a key role of vascular endothelial
growth factor receptor 1 in hemorrhagic telangiectasia type 2.
Now, this is an inherited genetic disorder where
haplo-insufficiency of the activin receptor-like kinase 1 gene,
ACVRL1, results in blood vessels that are prone to respond to
angiogenic stimuli, leading to the development of telangiectatic
lesions that can bleed.


                                               
First author, Dr Thalgott, corresponding author, Dr Lebrin from
Leiden University Medical Center and colleagues used ACVRL mutant
mice and found that vascular endothelial growth factor, or VEGF
receptor 1 levels were reduced, causing increased VEGF receptor 2
signaling that promoted sprouting angiogenesis, correcting the
abnormal VEGF gradient, by expressing membranal-soluble VEGF
receptor 1 in embryonic stem cells or blocking VEGF receptor 2
with antibodies in mutant mice, normalized the phenotype both in
vitro and in vivo.


                                               
Importantly, VEGF receptor 1 was reduced in the blood and skin
blood vessels of patients with hemorrhagic telangiectasia type 2
compared with H match controls, demonstrating an important role
of VEGF receptor 1 in these patients and explaining why their
blood vessels might respond abnormally to angiogenic signals.
These findings support the use of anti-VEGF therapy in
hemorrhagic telangiectasia type 2.


                                               
The next study suggests that hydroxychloroquine could be
repurposed to reduce the risk of rheumatic heart disease
following acute rheumatic fever. First author, Dr Kim,
corresponding author, Dr Wicks from Walter and Eliza Hall
Institute of Medical Research and University of Melbourne and
their colleagues analyzed the immune response to group A
streptococcus in peripheral blood mononuclear cells from an
Australian Aboriginal acute rheumatic fever cohort by a
combination of multiplex cytokine array, flow cytometric
analysis, and global gene expression analysis by RNA sequencing.


                                               
They then tested the widely used immunomodulatory drug,
hydroxychloroquine for its effects on this response. They found
that group A streptococcus activated persistent IL-1 beta
production and selective expansion of a specific group of T
helper 1 cells that produce GMCSF. Furthermore,
hydroxychloroquine limited the expansion of these group A
streptococcus-activated, GMCSF-producing T helper cells in vitro.


                                               
Gene transcriptional profiling of peripheral blood mononuclear
cells from patients with acute rheumatic fever showed dynamic
changes at different stages of disease. Given the safety profile
of hydroxychloroquine and its clinical pedigree in treating
autoimmune diseases such as rheumatoid arthritis where GMCSF
plays a pivotal role, the authors therefore proposed that
hydroxychloroquine could be repurposed to reduce the risk of
rheumatic heart fever following acute rheumatic fever.


                                               
The next paper identifies a new anchoring B genetic variant in
unrelated Han Chinese probands with ventricular tachycardia. In
this paper from co-first authors, Dr Zhu, Wang and Hu,
co-corresponding authors, Dr Hong from Second Affiliated Hospital
of Nanjing University, Dr Mohler from Ohio State University
Wexner Medical Center and colleagues, the authors identified the
first anchoring B variant, Q1283H, localized to the ZU5C region
in a proband with recurrent ventricular tachycardia.


                                               
Knocking mice with this variant showed an increased
susceptibility to arrhythmias associated with abnormal calcium
dynamics. The variant was associated with loss of protein
phosphatase 2A activity, increased phosphorylation of ryanodine
receptor, exaggerated delayed after depolarization-mediated
trigger activity, and arrhythmogenesis. Furthermore, the
administration of metoprolol or flecainide decreased the
incidence of stress-induced ventricular arrhythmias, representing
potential therapies for anchoring B variant-associated
arrhythmias.


                                               
Does variability in metabolic parameters affect health outcomes?
First author, Dr Kim, corresponding author, Dr Lee from Seoul
Saint Mary's Hospital College of Medicine and Catholic University
of Korea and their colleagues used nationally representative data
from the Korean National Health Insurance system, consisting of
more than 6.7 million people who are free of diabetes,
hypertension, or dyslipidemia and who underwent three or more
health examinations from 2005 to 2012 and were followed to the
end of 2015.


                                               
Variability and fasting blood glucose and total cholesterol,
systolic blood pressure and body mass index was measured using
the coefficient of variation, standard of deviation, variability
independent of the mean, and average real variability. They found
that a high variability in fasting glucose and cholesterol,
systolic blood pressure and body mass index was associated with a
higher risk for all-cause mortality, myocardial infarction, and
stroke. Variabilities in several metabolic parameters had
additive associations with the risk of mortality and
cardiovascular outcomes in the general population.


                                               
These findings suggest that treatment strategies to reduce
fluctuations in metabolic parameters may be considered another
goal to prevent adverse health outcomes.


                                               
How much exercise over a lifetime is necessary to preserve
efficient ventricular arterial coupling? First author Dr Hieda,
corresponding author Dr Levine from Texas Health Presbyterian
Hospital Dallas and University of Texas Southwestern Medical
Center and colleagues studied 102 seniors and grouped them based
on their 25 years of exercise training history. The dynamic
Starling mechanism was estimated by transfer function gain
between beat-by-beat changes in diastolic pulmonary artery
pressure and stroke volume index.


                                               
They found that there was a graded dose-dependent improvement in
ventricular arterial coupling with increasing amounts of lifelong
regular exercise in healthy older individuals. Their data
suggested that the optimal does of lifelong endurance exercise to
preserve ventricular arterial coupling with age appeared to be at
least four to five sessions per week. The sufficient lifelong
endurance exercise was effective for maintaining the normal
dynamic Starling mechanism, left ventricular compliance, and
arterial compliance with aging, all of which may lead to
favorable effect on cardiovascular stiffness or function.


                                               
And that brings us to the end of our summaries this week. Now,
for our feature discussion.


                                               
Transcatheter aortic valve replacement is taking over the
interventional world. It's really rapidly growing, and we're
increasingly using it for the treatment of aortic stenosis. It
was initially used for inoperable and high-risk patients but now
is indicated even in the treatment of intermediate-risk patient,
and even low-risk patients are being enrolled into current
trials.


                                               
So, with TAVR being used for low- and intermediate-risk patients,
the longer-term results of this treatment involved your abilities
becoming more and more important. Well, gratefully, we have
today's feature paper, and it describes the five-year clinical
outcomes and valve durability of the FRANCE-2 Registry.


                                               
I'm so pleased to have with us the corresponding author, Dr
Martine Gilard from University Hospital of Brest in France, we
have our editorialist, Dr Anita Asgar from Montreal Heart
Institute, and we have our associate editor, Dr Dharam Kumbhani
from UT Southwestern.


                                               
Martine, congratulations on this largest cohort of high-risk
patients and long-term outcomes. Could you please tell us what
you found?


Dr Martine
Gilard:           
Yes, and I'll just quote, actually, to have a follow-up of five
years. We have 1,200 patients arrive at five years after rotation
of TAVI. Each patient was a high-risk patient because it was at
the beginning of each treatment, and in this time, it's only the
high-risk patient was implanted with TAVI, and actually, we can
follow this 1,200 patients, 50% of these patients of these
patients have an echography because when we analyze these
patients, we have an echography at five years, and the patients
who have not echography at five years, the only difference is the
age.


                                               
It's very old patient. It's very difficult to make this
echography on this patient to come back in our center, so it's
why there is not all the patient who have an echography at five
years.


                                               
But our patients who have an echography, we can see that it's a
very, very good result at five years. There is always the same
area, just after before, of the valve. There is the same
gradient. There is not a sign of deterioration.


                                               
As you know, we have some guidelines published last year about
how we asked to define deterioration of the valve, surgical or
TAVI, and if we apply this new recommendation, we saw that in
this largest cohort, at five years, there is only 13% of patient
who have some sign of deterioration, and of these patients, we
never need to make another valve in valve because the
deterioration was not so important, and patient leave with this
valve like that. There is no necessity to make a new valve in
valve, so at five years of this very high-risk patient treated by
TAVI, there is no necessity to implant a second valve because the
valve deterioration. It's a very, very important message.


Dr Carolyn
Lam:               
Thank you, Martine. Indeed, an important message. And Anita, you
wrote a beautiful editorial about it. First, could I ask you to
frame the issue? I mean, is there any reason we would expect the
durability to be any different from a surgical replacement?


Dr Anita
Asgar:                 
I think that's a great question, Carolyn, and I congratulate
again Martine and her team for doing a fantastic job to add some
very important results to the clinical literature on TAVI. Five
years is relatively early to see structural valve deterioration,
so in a sense, it's not surprising, and we would consider this
sort of medium-term follow-up rather than really long-term
durability, but very reassuring that in a high-risk population of
patients, that TAVR performs very well in this population of
patients and as mentioned, is very low to the dynamic structural
valve deterioration.


                                               
One question I have for Martine is, as you mentioned, there was
only about 12% that had some evidence of structural valve
deterioration hemodynamically, but this didn't result in another
procedure, and I wonder if you could explain a little bit about
that, whether it's the hemodynamic dynamic value, and yet there's
a clinical indication for re-intervention. How do you incorporate
the two?


Dr Martine
Gilard:           
It's actually hemodynamic deterioration, there is some form of
regurgitation. However, there is no need or clinical indication
to make another intervention. So, if you compare this research to
the bioprostheses surgical paths, the only one who have, at five
years, no need to make a re-intervention appearing rotated, which
is a valve, a surgical valve we have a longer bioprostheses
surgical path.


                                               
So, if we compare this best bioprostheses surgical valve, we have
sustained results at five years. At five years, we have no need
to make a re-intervention because the deterioration was not so
important or as needed for clinical evidence as a need to make a
new intervention.


Dr Anita
Asgar:                 
So, there were some increased rates of heart failure in those
patients with structural valve deterioration in your paper, and I
know that in the paper you did mention that this is not an
adjudicated outcome, and there wasn't a VARC definition for heart
failure, but what's your interpretation of increasing heart
failure events in these patients with structural valve
deterioration?


Dr Martine
Gilard:           
We have no real definition about that. We know that there is
another registry. We say that there is an increasing of heart
failure, and during the follow-up, and the result of this heart
failure increase in mortality. There is an increasing of heart
failure, but the number of these patients, there is more. So I
don't know if this due to because patient is a high-risk patient,
or it's because of the TAVI, but it's very difficult actually to
have a real explanation about that.


Dr Carolyn
Lam:               
Thanks, Anita and Martin. Dharam, could you share some of the
thoughts and the discussions that were going on behind the scenes
with the editors when we saw this paper?


Dr Dharam Kumbhani:   Professor Gilard, this was a
really excellent paper. We really appreciated you sending it to
us, and I think for us, the fact that this was a very large
cohort, the largest published cohort that has gotten to five
years in a TAVR population, in a multicenter study, and having
very good follow-up up to five years, with these patients is
always this competing hazard that you want to know what the valve
is doing at five years from an echocardiographic and hemodynamic
perspective, but there's such a high competing hazard of death,
just given the population that you're enrolling, and still, you
had one of the largest echo follow-ups on these patients, so we
want to congratulate you on the study and really a monumental
endeavor, and so really great, great work there.


                                               
And I think this is, exactly some of the questions that I think
we had and I'm sure that the audience would have as well, I guess
the one other question I have, and it's not really a question
about your paper. So the median Euro score is 21 in this study,
approximately 21, so that's obviously gonna, consistent with the
patients that are being enrolled at that time between 2007 and
2012, which were predominantly high-risk and inoperable patients.
Can you talk to us a little bit about the landscape of, how is
TAVR practice in France as a society or from the regulatory
standpoint, what are the benchmarks that you have achieve as you
move towards low-risk now? Because intermediate-risk, I'm
assuming is a [inaudible 00:20:16], so could you talk to us a
little bit about the landscape there?


Dr Martine
Gilard:           
Yes. In France, it's difficult because we have the authority to
follow, not immediately, the ESC recommendations, so actually in
France, we are allowed to implant only patients with high risk,
patients with complication of surgery, and actually just since
one year, patients with automatic risk, but we have no
authorization to implant patient with low risk.


                                               
However, the most important fact is the heart team, and if they
write. Because we need to have something written, and if they
write, if they explain that it's necessary to implant a patient
at low risk because of some point while not including the risk
score or it's very difficult to explain, for example, frailty or
something, we can implant a patient with low risk.


                                               
But normally actually, it is only for complication or high risk
and for intermediate risk like the recommendation of the ESC.


                                               
So the rate of implantation in France increased because we
implant only 2,000 people per year, but actually, in 2017, we
have implanted 10,200 patient, and this year, we think that we
implant 12,800 patients, so as the number of patients increase,
the number of patients who have a very high risk decrease because
there is a futile indication, and we have a lot of futile
indication, so we doesn't implant patient while too high-risk,
and we select the most majority of patient implanted in France
was high-risk but also intermediate-risk.


Dr Dharam Kumbhani:   So, you think you're implanting
more intermediate, like that is a bigger population that is
getting TAVIs right now in France?


Dr Martine
Gilard:           
Yes, exactly.


Dr Carolyn
Lam:               
How about perspectives from Montreal? What do you think the
implications of this findings from today's paper in relation to
the types of patients that you might perform this in now?


Dr Anita
Asgar:                 
For us, this is exceptionally reassuring, and as Martine has
said, I mean, we have transitioned as well away from that very
inoperable cohort C type of patient to more your higher-risk
patient or intermediate, and to be honest, everyone over the age
of 80 in Canada essentially is getting a TAVR.


Dr Carolyn
Lam:               
Oh, wow.


Dr Anita
Asgar:                 
Because regardless of their risk, and we've been very aggressive
with that because trying to get patients back to an appropriate
quality of life is very important, and to seeing this very
reassuring data is telling us that, as she has already mentioned,
we have reached the standard, at least in midterm follow-up as
the gold standard of surgical valve replacement, and so
structural valve deterioration is not as big a concern.


                                               
I think we still however need longer-term data when we're looking
at lower-risk patients, and lower-risk patients, let's remember,
are not 60-year-olds. They're the 75-year-old, perhaps. But we're
still gonna need some more data, but it's very reassuring, and
patients are asking for it and are really advocating on their
behalf to have a less invasive approach, and I think we can say
now with more certainty that we know after five years, your
chance of structural valve deterioration is actually quite low,
and so I think that's very helpful from our point of view.


Dr Carolyn
Lam:               
I love that, Anita, and it's so consistent with the title of your
editorial, "Closing in on the Finish Line". Love it, love it, and
recommend all listeners pick it up and have a good read. Dharam,
I want to leave the last words to you. What do you think are the
implications of this paper?


Dr Dharam Kumbhani:   Well, I think that, as Anita
said, this is very encouraging results that, in this kind of
extreme and high-risk patient cohort, that there appear to be no
medium- to long-term signals of structural valve degeneration,
that the biggest hazard from this procedure is all upfront, and
after that, it's pretty much, it's as we have seen with surgery,
that after that, the actuarial rates come back to what you would
expect.


                                               
If they didn't have aortic stenosis and then they would die from
whatever causes they had. Now obviously, that wasn't tested, but
it seems like looking at the curves, that that seems like what's
going on, so I think they've done a great service to our TAVR
community in terms of showing us these results in very large,
multicenter cohorts from France.


Dr Carolyn
Lam:               
Thank you so much for joining us today. Thank you, listeners.
You've been listening to Circulation on the Run. Don't forget to
tune in again next week.


                                               
This program is copyright American Heart Association, 2018.