Circulation July 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. We're your
co-hosts, I'm Dr Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr Greg
Hundley:            
And I'm Dr Greg Hundley: Hundley, Associate Editor from the
Pauley Heart Center in Richmond, Virginia at VCU Health. Well
Carolyn, our featured article this week addresses the age at
which to initiate clinical screening of relatives for
hypertrophic cardiomyopathy. Our guidelines suggest screening of
relatives from age ten and onwards but data are lacking to
substantiate this suggestion. I look forward to the authors'
discussion of their findings regarding initiation of screening in
children. For now though, do you have an article that you'd like
to share?


Dr Carolyn
Lam:               
You bet, Greg. So, the first paper I chose really demonstrates
that patients inducible pluripotent stem cells or IPSC cardio
derived myocytes can be used as a disease modeling platform to
delineate the functional mechanisms that underlie cardiac
hypertrophy and in this particular case they looked at Noonan
Syndrome and showed that how these techniques can be subsequently
used to identify novel molecular and genetic therapeutic targets.
So, Greg, here's your quiz. The genetics of Noonan Syndrome.


Dr Greg
Hundley:            
I remember it was on our board exam.


Dr Carolyn
Lam:               
Let me tell you about it. So more than 90% of patients with
Noonan Syndrome have a mutation in the hinge region CR2 domain of
Raf-1 and they exhibit severe hypertrophic cardiomyopathy for
which there is no treatment. Authors, Dr Jaffrey from Cornell
University and Dr Kontaridis from Masonic Medical Research
Institute in Utica in New York and their colleagues used Noonan
Syndrome Raf-1 patient and CRISPR corrected IPSC cardiomyocytes
to recapitulate the Noonan Syndrome cardiac phenotype.


                                               
These Noonan Syndrome IPSC derived cardiomyocytes exhibited the
same hypertrophy and myofibrillar disarray that's really observed
in Noonan Syndrome patient hearts, so mechanistically the authors
showed that activation of mitogen-activated protein kinase or
mech-1 or -2, but not the extracellular regulated kinase, which
is ERK1 or 2 triggered abnormal cardiomyocytes structure and
conversely ERK5 mediated increased cell size in these Noonan
Syndrome mutant IPSC derived cardiomyocytes.


                                               
RNA sequencing further identified genes dysregulated in the
Noonan Syndrome cardiomyocytes that may underlie hypertrophic
cardiomyopathy downstream if the mech-1 or -2 and ERK5 genes.


Dr Greg
Hundley:            
So, Carolyn, that's a lot of genetic information, so what can I
take home as I think about this further and what may come down
the line as we manage patients with Noonan Syndrome?


Dr Carolyn
Lam:               
Thanks, Greg. The real take home message is that these pathways
could serve as novel therapeutic targets to treat hypertrophic
cardiomyopathy in patients with Noonan Syndrome and Raf-1
mutations. Overall, the elucidation of rare disease mechanism of
hypertrophic cardiomyopathy may further unravel and reveal causes
of other more common idiopathic congenital disorders and
hypertrophic diseases.


Dr Greg
Hundley:            
Oh, very good. Well, I'm going to switch gears and talk a little
bit about infective endocarditis prophylaxis and this article
comes from Pallavi Garg at the London Health Scientist Center.
Carolyn, as you may recall, given the lack of proven efficacy and
concerns about the perceived risks of antibiotic prophylaxis like
development of antibiotic resistance, the American Heart
Association in 2007 and the European Society of Cardiology in
2009 published revised guidelines recommending cessation of
antibiotic prophylaxis prior to dental procedures for patients at
moderate risk of infective endocarditis while continuing the
practice in high risk patients. This Canadian study was conducted
from 2002 to 2014 among all adults and those at high and moderate
risk for infective endocarditis and they were stratified by age.
Prescriptions for antibiotic prophylaxis were obtained from the
Ontario Drug Benefit Database for adults 65 and older and
outcomes regarding antibiotic prophylaxis prescription rates and
the incidents of infective endocarditis related hospitalization
were assessed.


Dr Carolyn Lam:
               
Ooh, interesting. What did they find?


Dr Greg
Hundley:            
The authors found a sustained reduction in antibiotic prophylaxis
prescriptions among individuals at moderate risk for infective
endocarditis that coincided with the change in guidelines. In
contrast, while there was a decreasing trend in antibiotic
prophylaxis among individuals at high risk of infective
endocarditis and a minimal drop following the guidelines
released, the overall rates of prophylaxis prescribing in this
group continued to climb since early 2007, and collectively,
these findings suggest that appropriate uptake of the revised AHA
guidelines occurred.


                                               
Furthermore, over the thirteen-year study period, the authors
identified an increase in hospitalizations for new episodes of
endocarditis approximately three years after the AHA guidelines
were revised. This timeline along with the rise of endocarditis
incidents in both the high and moderate risk groups suggests that
this observed increase in endocarditis is likely unrelated to the
change in the prescribing practice of antibiotic prophylaxis.
This conclusion is further supported by the overall decrease in
endocarditis cases attributable to streptococcal infections over
time, a finding contrary to what might be expected as a result of
the reduction in antibiotic prophylaxis.


Dr Carolyn
Lam:               
Oh, very interesting, Greg. At first a little bit scary and then
after when you described it more, it does seem a little bit more
reassuring. Very interesting. Well, thank you. My next paper
deals with functional tricuspid regurgitation, which as you know
is really common in heart failure with reduced ejection fraction
or HFrEF and mostly consequent to pulmonary hypertension.
However, what is the access mortality associate with functional
tricuspid regurgitation in HFrEF? Well, this paper from Dr
Maurice Serrano from Mayo Clinic and colleagues looked at all
Mayo Clinic patients from 2003 to 2011 diagnosed with heart
failure stage B and C and an ejection fraction less than 50% who
had functional tricuspid regurgitation grading and systolic
pulmonary artery pressure measured by Doppler echocardiography.


                                               
Now among more than 13,000 patients meeting these inclusion
criteria, functional tricuspid regurgitation was detected in 88%.
Functional tricuspid regurgitation was independently associated
with more dyspnea, more impaired kidney function, and lower
cardiac output. For the long term outcomes, the higher the degree
of functional tricuspid regurgitation compared with a group with
trivial tricuspid regurgitation was independently associated with
a higher mortality hazard. The five year survival was
substantially lower with increasing severity of tricuspid
regurgitation so it was 68% on average for trivial functional
tricuspid regurgitation versus 34% for severe functional
tricuspid regurgitation.


                                               
Importantly, this access mortality observed with moderate or
severe functional tricuspid regurgitation was independent of
pulmonary hypertension and any other clinical characteristics.


Dr Greg
Hundley:            
Hmm, interesting but Carolyn, wouldn't we expect this?


Dr Carolyn
Lam:               
You know what, you may expect it, but this is really the largest
series, I think, that has shown this and shown this in the
systematic way that functional tricuspid regurgitation in and of
itself may play an important pathophysiologic role and thus, may
represent a potential therapeutic target in HFrEF. In other
words, the present study really advocates for a trial to test
treating functional tricuspid regurgitation in patients with
HFrEF.


Dr Greg
Hundley:            
Oh wow, you really put that in great perspective, Carolyn. Well,
your reward is   going to be a quiz.


Dr Carolyn Lam:
               
Oh my gosh, Greg.


Dr Greg
Hundley:            
We're going to talk about ...


Dr Carolyn Lam:
               
What now?


Dr Greg
Hundley:            
Caveolin-1, an atherogenesis and nitric oxide and this is from
Professor Carlos Fernandez Hernando at the Yale University School
of Medicine. Okay, multiple choice. What are caveolae? Now I'm
going to give you some choices, you get to pick A. Are they
crypts within the walls of vessels. B. Crypts within the
membranes of endothelial cells. Or C. Crypts within the border
zones of infarcts.


Dr Carolyn
Lam:               
Wait a minute, Greg. I'm not even sure we're pronouncing it the
same. You're asking about caveolae like ... Potato potata.
They're invaginations of cell membranes, that's all I know.


Dr Greg
Hundley:            
Oh wow, fantastic. This study focused on the effect of
Caveolin-1, a protein integral to the formation of caveolae. The
investigators found in a series of mouse experiments that A. The
athero-protection observed in mice lacking Caveolin-1 is
independent of endothelial nitric oxide synthase activation and
nitric oxide production. B. Endothelial Caveolin-1 controls
lipoprotein infiltration in vascular inflammation in early stage
atherosclerotic lesion. C. Endothelial Caveolin-1 promotes
pro-atherogenic matrix deposition leading to endothelial cell
activation in atheroprone regions of the aorta and finally, D.
Atheroprone regions of the aorta are characterized by increased
intracellular and basolateral caveolae distribution in
endothelial cells compared to athero-resistant areas.


Dr Carolyn
Lam:               
Wow, I like the way you broke that down into four points, but
could you summarize what it means clinically?


Dr Greg
Hundley:            
Yeah, so I think if you had to summarize all of this in a
sentence, perhaps the suppression of Caveolin-1 expression in
endothelial cells might prevent the progression and promote the
regression of atherosclerosis so in the future perhaps an
interesting target to treat atherosclerosis. Well, now Carolyn, I
guess we should proceed to that talk with our featured
discussion.


Dr Carolyn Lam:
               
Absolutely. Thanks, Greg.


                                               
Hypertrophic cardiomyopathy is an inheritable myocardial disease
with age-related penetrance. Current guidelines recommend that
clinical screening of relatives start from the age of ten years
onwards by the European Society of Cardiology and twelve years
onwards by the American College of Cardiology or American Heart
Association. There are of course caveats for earlier screening
but the clinical value of this approach has really not been
systematically evaluated. That is until today's feature paper and
we are so pleased to be here discussing it. This is Greg Hundley
and Carolyn Lam and we're your co-hosts for Circulation on the
Run. So happy to welcome Dr Juan Pablo Kaski who's the
corresponding author of today's feature paper from Great Ormand
Street Hospital in London and we also have Dr Gerald Greil,
Associate Editor from UT Southwestern.


                                               
Welcome, everyone. Juan, if you don't mind, could you start by
summarizing this very important study of yours?


Dr Juan Pablo Kaski:       
Thank you very much. Hypertrophic cardiomyopathy is a genetic
muscle condition that is characterized by hypertrophy and is most
commonly inherited as a dominant trait. Previous studies have
suggested that in familial disease at least ventricular
hypertrophy doesn't usually present until adolescence and this
has led to the current guidelines which do not recommend routine
screening of children below the age of twelve according to the
American guidelines below the age of ten and the European
guidelines for hypertrophy cardiomyopathy but own clinical
experience was different and suggested that perhaps sarcomeric
disease and familial disease could present in younger children,
so what we aimed to do with this study was to assess the validity
of this approach and tried to assess the yield of clinical
screening in children from families of hypertrophic
cardiomyopathy.


Dr Juan Pablo Kaski:        We
took our collective experience in our institution over a period
of many years and recruited just on the 1,200 consecutive
children all aged less than eighteen years at the time of initial
assessment coming from just under 600 families and these were
children who were referred for clinical screenings because a
first degree relative had been diagnosed with hypertrophic
cardiomyopathy. What we found was that in 5% of these children
and in fact, in 8% of the families that we screened, we were able
to pick up early phenotypic features of hypertrophic
cardiomyopathy. In 72% of patients, we made a diagnosis before
the age of twelve, so before current clinical screening
guidelines we'd recommend and importantly, a third of these
patients during follow up had a change in their management as a
result of the diagnosis. Their medication was commenced, they
underwent procedures or implantations of defibrillators.


Dr Greg
Hundley:            
Juan, this is Greg Hundley and I was wondering when did the
participants that were enrolled experience events? Did those that
were say under fourteen or even under twelve, did they experience
events relative to those that were a little older?


Dr Juan Pablo Kaski:       
The events that our participants experienced were relatively few.
Many of these occurred during the childhood age but some occurred
once the children had transitioned into the adult age. We did
look to see whether there was any difference in terms of early
diagnosis and subsequent events, but we didn't find anything, we
didn't identify two separate populations in that respect.


Dr Greg
Hundley:            
And then did you perform genetic analyses? I know you described
phenotypic characterization of the patient population but how
about genetically? What results did you find there?


Dr Juan Pablo Kaski:       
The main aim of the study really was to determine a yield of
clinical screenings, so this is a reflection of a real-world
practice where genetic testing may not necessarily be routinely
available. Having said that, we did have genetic data in a third
of our families and in fact, in maybe 70% of those children who
made clinical diagnosis of hypertrophic cardiomyopathy was made
and what we find in those individuals who have undergone genetic
testing is that the vast majority of those had mutations in
sarcomeric protein genes and pathogenic or likely pathogenic
variants in sarcomeric genes in just under 70% and these were
well characterized mutations that are very similar to those that
are seen in adolescence or adult onset hypertrophic
cardiomyopathy.


                                               
I think what was interesting about these genetic results is that
we seem to have identified a population of early onset sarcomeric
disease that genetically appears to be indistinguishable from a
sort of later onset adult disease but with the clinical
presentation and natural history curve shifted somewhat to the
left.


Dr Greg
Hundley:            
Gerald, just switching over, can you tell us some of your
thoughts about how the results of this study will impact clinical
practice, both in the European countries as well as U.S.?


Dr Gerald
Greil:                
I mean, I was obviously delighted to see the study being
submitted to circulation because there's a very important message
particularly for pediatric cardiologists which is potentially
influencing the guidelines and Dr Kaski may comment on this as
well as the next step meaning that it seems like screening
patients older than ten or twelve years and once again, there's a
slight discrepancy between the European and U.S. guidelines,
seems to be ... Can be questioned and potentially we should
screen these patients earlier.


                                               
Another amplification of this study is that we should think about
how much genetic screening can be an essential tool in our
methods in looking at these patients and I want to point out that
because of these discrepancies we also initiated an editorial
letter for this publication done by Dr Ommen and by Dr Mital kind
of pointing out there needs a lot of work to be done maybe even
including rewriting the current guidelines.


                                               
There's another paper that came out recently in European Society
Cardiology, the European Heart Journal about a similar topic so
it's something which is very, very heavily discussed in our
community. We think how we are looking at these patients and how
we're following them up.


Dr Greg
Hundley:            
What would you suggest are next steps for the world community in
this space in regards to modifying those guidelines?


Dr Gerald
Greil:                
I think there's now enough literature around which suggests that
we should look at these patients earlier and screen them earlier
on both sides in European, in the U.S., in the Asian world, and
ideally these two groups should sit together and write combined
guidelines. It's still interesting that the European and U.S.
guidelines are slightly different in that we're talking about a
similar group of patients, so I'm very, very delighted to see
that this is coming up in the national literature as a new topic
and I think everything is open now to rethink this topic and
rewrite these guidelines.


Dr Greg
Hundley:            
Do you think prospective studies would be necessary because I
believe, and Dr Kaski please weigh in here, this was a
retrospective review, and do you think there could have been
triggering circumstances that prompted early screening? I mean,
would a next step be some sort of prospective registry?


Dr Gerald
Greil:                
I mean definitely that's the next step. I think we have enough
data material around once again to rethink the strategy which age
these patients should be looked at. A prospective registry and Dr
Kaski can probably comment on it better than I can, I think that
something which is a logical next step and there may be even
something being on the way to make this happen.


Dr Juan Pablo Kaski:        I
agree. I think further validation and confirmation of these data
from prospective studies would be extremely helpful. I think one
of the things that we need to bear in mind is the potential cost
implications of expending screening to ever increasing
populations and so perhaps an additional further step would be to
try to refine the screening tools so that we are able to identify
clinical by a chemical of those individuals who are more likely
to present in childhood and perhaps set a target screening
towards that population.


                                               
I can just go back to one of your sort of previous points also
about a potential bias and it is true that these patients were
referred for clinical screening at a time when clinical
recommendations do not suggest that this is necessary and
although we didn't specifically in this cohort look at those that
would have fulfilled current early screening criteria, the vast
majority of the patients were asymptomatic at the time that they
were referred. We also looked to see whether there was any link
between those individuals who had a family history of early onset
disease and an early diagnosis, and that was the only factor that
came up as potentially significant so perhaps the current
guidelines that do recommend considering earlier screenings if
there's a family history of childhood disease are still
applicable.


Dr Carolyn
Lam:               
That was just an amazing interview, by the way. I've learned so
much and thank you so much for publishing this very important
paper with us.


                                               
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 2019.