Circulation July 2, 2019 Issue

Dr Greg
Hundley              
Welcome back everyone from our week hiatus for this July 2nd
issue of Circulation On the Run. I'm Dr Greg Hundley, from the
Pauley Heart Center at VCU health in Richmond, Virginia.


Dr Carolyn
Lam:               
And I'm Carolyn Lam, associate editor from the National Heart
Center and Duke National University of Singapore. So good to be
back, Greg.


Dr Greg
Hundley              
Absolutely. So Carolyn, our featured articles going to focus on
amyloid and transthyretin amyloid is recognized in middle age and
older individuals with increases in LV mass and heart failure.
And in our featured article from the United Kingdom, Dr Gilmore
and colleagues are going to discuss the natural history of this
disease and compare outcomes of those with acquired versus
hereditary forms of the disease. But before we get to that
interview, how about we discuss several other original articles?


Dr Carolyn
Lam:               
For sure, Greg. Thanks. I want to pick two genetic papers in this
issue. They're really exciting. The first one is actually the
first study to consider the association between rare genetic
variance in a large set of cardiomyopathy genes and the
occurrence of cancer therapy induced cardiomyopathy. So this
paper is from co-corresponding authors, Dr Garcia-Pavia from
hospital Universitario Puerta de Hierro from Madrid, and Dr
Christine Seidman from Harvard Medical School in Boston,
Massachusetts. The authors studied 213 patients with cancer
therapy induced cardiomyopathy from three cohorts. The first
retrospectively recruited adults with diverse cancers, the second
prospectively phenotyped breast cancer patients. And then the
third prospectively phenotyped children with acute myeloid
leukemia. They showed an increased prevalence of rare variants in
cardiomyopathy genes, particularly the truncating variants of the
TTN gene in both adults and pediatric cancer patients with cancer
therapy induced cardiomyopathy. They confirmed the human genetic
data with experimental analyses showing that anthracyclines
induced protracted left ventricular dysfunction in mice with
truncating variants of TTN genes but not in the wild type mice.


Dr Greg
Hundley              
Aha. So what are the clinical implications of this study,
Carolyn?


Dr Carolyn
Lam:               
Well, the findings show that variance in cardiomyopathy genes
contribute to cancer therapy induced cardiomyopathy
susceptibility among adult and pediatric cancer patients. And
thus the identification of genetic risk factors really opens the
door to new opportunities to define patients at high risk of
cancer therapy induced cardiomyopathy and associated adverse
outcomes.


                                               
I want to go onto the next paper because it's so related. It's
another genetic paper. This time looking further at the
truncating variants of the TTN genes and a very novel approach,
they aim to assess a genomics first approach to assess the
consequences of these TTN variants. So, this was from
corresponding author Dr Zoltan Arany from Perelman School of
Medicine in University of Pennsylvania where he and his
colleagues reviewed whole exome sequence data for more than
71,000 individuals to identify anyone with truncating variants of
TTN genes. They further selected individuals with these variants
in exons highly expressed in the heart and using a linked
electronic health record, they evaluated the associations of
these truncating variants of TTN genes with the diagnosis and
quantitative echocardiographic measures. They also reviewed data
from the Jackson Heart study to validate specific analyses for
individuals of African ancestry.


Dr Greg
Hundley              
Interesting. So we're hearing a little bit about different
ancestry and TTN genes. What did they find?


Dr Carolyn
Lam:               
So, I should have first clarified that that first look was in
individuals of European ancestry. And they found there that the
individuals of European ancestry identified through this genomics
VERSE approach had a much greater odds of developing dilated
cardiomyopathy and had lower left ventricular function than their
peers, whether or not a clinical diagnosis of dilated
cardiomyopathy was present. They also found that the association
of the TTN variants and dilated cardiomyopathy was much weaker in
individuals of African ancestry. So in summary, truncating
genetic variants of TTN had a measurable effect in large clinical
populations with respect to both strong associations with
cardiomyopathy and with associations with quantitative
differences in cardiac structure and function. Given the caveat
though, that these association appeared strongest in individuals
of European ancestry. So Greg, what did you have?


Dr Greg
Hundley              
Well, Carolyn, the overlap of inflammatory processes operating in
atherosclerosis and the rich presence of macrophages within
plaques make macrophages a strong candidate for therapeutic
targeting in atherosclerosis. And so this study comes from Levent
Akyürek at the Institute of Biomedicine and involves targeting
filament A to reduce macrophage activity in atherosclerosis. So
filament A is a large actin binding protein that has been
implicated in atherosclerosis and this study tested the
hypothesis that targeting filament A in macrophages would impair
atherosclerosis in vivo in mice and the investigators evaluated
the expression of filament A in human atherosclerotic plaques.


Dr Carolyn
Lam:               
Huh, interesting. So what did it show?


Dr Greg
Hundley:            
Well, in humans, expression of filament A is increased in
macrophages and advanced atherosclerotic plaques of human carotid
arteries. In mice, in the absence of filament A, macrophages
displayed impaired migration, proliferation and lipid uptake and
secreted lower levels of inflammatory IL 6, also lack of filament
A and macrophages in vivo reduced aortic plaque size and
atherogenic mice.


                                               
There were additional mechanistic findings and that the C
terminal fragment of Filament A produced by calpain cleavage
regulated IL 6 secretion in macrophages and treatment with
calpeptin, which inhibits calpain cleavage, reduced aortic plaque
size and atherogenic mice. And so therefore, filament A might
serve as a prognostic biomarker and atherogenesis and perhaps
targeting the C terminal proteolytic fragment of filament A could
be a strategy to reduce inflammation and atherosclerotic plaque
development. Carolyn, I've got another paper, but guess what?
This one has our first quiz of the academic new year. This is a
paper about Nexclin, and it discusses a new component of
junctional membrane complexes required for cardiac T-tubule
formation. The corresponding authors are led by professor Zhou
Shen from the University of California, San Diego. So, Carolyn in
this quiz, what is a T-tubule?


Dr Carolyn
Lam:               
Greg, that is mean! T-Tubules, something inside the cell.
Something to do with membranes folding over.


Dr Greg
Hundley              
Yeah, you know this is one of those, it's not multiple choice.
It's an open ended question. You need your little blue book.
You've got to write the answer. So T, or transverse, tubules are
extensions of the cell membrane that penetrate into the center of
cardiac muscle cells and interact with the sarcoplasmic reticulum
to facilitate calcium release and thus help modulate myocardial
contraction. T-tubule uncoupling and remodeling are known
features of heart failure.


Dr Carolyn
Lam:               
Alright, so that's T-tubules. Guess what Greg, I'm going to ask
you before you ask me. So, what's Nexilin?


Dr Greg
Hundley              
I read the paper like a good student of the American Heart
Association. This was answered by the investigative team of Chen
and his associates. Nexilin has been identified as an actin
binding protein and multiple mutations in the nexin gene are
associated with cardiac diseases. In this study, Nexilin was
required for initiation of T-tubule invagination and overall
T-tubule formation, with a loss of next sullen leading to
impaired calcium handling. Clinically, these results identified
Nexilin as a new possible target for T-tubule remodeling and
provide mechanistic insight into molecular pathways leading to
cardiomyopathy in patients with mutations in Nexilin. So Carolyn,
great job on our first quiz of the academic new year. And how
about we move on to that featured discussion?


Dr Carolyn
Lam:               
Absolutely.


Dr Greg
Hundley              
Welcome everyone to our featured article discussion on this July
2nd and we are going to discuss with Dr Julian Gilmore from
London, and our editor Dr Justin Grodin from Dallas, regarding
amyloid. And Julian, I understand this particular study you have
investigated a natural history of transthyretin amyloidosis
cardiomyopathy. Can you tell us a little bit about transthyretin
amyloid as opposed to light chain amyloid? And then also I think
there's two types of transthyretin amyloid, both a hereditary and
then a wild type.


Dr Julian
Gilmore:           
Amyloidosis is a disorder of protein misfolding, and there are in
fact many different proteins that can misfold and form amyloid
fibrils. When they form fibrils they become insoluble and tend to
build up and cause damage to whichever organ they're depositing
in. Two of the proteins that form amyloid fibrils in humans in
vivo are transthyretin, known as TTR for short, or immunoglobulin
light chains, known as immunoglobulin light chains, and those two
proteins cause transthyretin amyloidosis and AL amyloidosis or
immunoglobulin light chain amyloidosis respectively. Those are
the main two types of amyloid that affect the heart or cause a
cardiomyopathy and they behave very differently in terms of their
natural history in that AL amyloidosis is a very aggressive,
rapidly fatal cardiomyopathy if untreated. Whereas cardiac
transthyretin amyloidosis tends to be a more gradual albeit
progressive cardiomyopathy.


                                               
Transthyretin amyloidosis, as you alluded to, can either be
acquired, known as wild type or hereditary and in the hereditary
version it's associated with mutations in the transthyretin gene
of which there are more than 130 now that are recognized to cause
disease. The wild type version of the disease, the non-hereditary
version of the disease, is now an increasingly recognized cause
of heart failure, mainly in older individuals and particularly
older males. And the hereditary version essentially remains a
rather rarer disease, although the mutation that is associated or
it is associated with a risk of developing this disease occurs in
certain populations and in particular occurs in 4% of people of
African descent, as a particular genetic mutation that occurs in
4% of individuals of African descent. So and that is associated
with risk of developing this hereditary transthyretin
cardiomyopathy.


Dr Greg
Hundley:            
And so, there's the UK National Amyloidosis Center. Tell us a
little bit from that center, what did you do with this particular
study in terms of its design and what were your results?


Dr Julian
Gilmore:           
Essentially the UK National Amyloidosis Center is the single
center in the UK, which is commissioned centrally to diagnose and
type, stage, and provide treatment FYS for patients with
amyloidosis. And that includes all parts of amyloidosis. We
studied a large number of patients with cardiac transthyretin
amyloidosis, so cardiac ATTR amyloidosis, who referred to our
center and studied them longitudinally, if you like, over the
course of many years. So this was a natural history study for a
condition for which at the time of the onset of the study and
until the end of the study there was no disease modifying
treatment and essentially what we found is that there was a great
delay in diagnosis amongst most patients diagnosed with the
disease and in fact the median number of attendances in hospital
for patients diagnosed with the disease before they were actually
diagnosed with 17 which is quite amazing and unsurprisingly in a
gradually progressive disease, by the time they were diagnosed,
their quality of life was very poor.


                                               
We found that their quality of life symptoms gradually progressed
and that they became more and more functionally impaired and had
relatively poor survival with a median survival of somewhere in
the region of five years. What we did find is that patients with
a particular type of hereditary, ATTR amyloidosis, the type that
I alluded to earlier, the mutation for which is present in 4% of
people of African ancestry, he planted the V122I mutation.
Patients carrying that particular mutation actually have more
aggressive disease and survive for shorter than patients with the
wild type disease.


                                               
So, 17 hospitalizations before diagnosis and the proceeding three
years. Were there factors in your study that you could identify
that we should now be looking for to try and make this diagnosis
earlier?


                                               
Absolutely. So one of the reasons for not diagnosing the
condition is basically the poor sensitivity and specificity of
echocardiography, which is generally the first investigation that
a cardiologist will request when a patient presents with symptoms
of heart failure. There are some particular features on
echocardiography that can provide clues such as strain
measurement on tissue doppler imaging, where one can get a
bullseye pattern, that's been reported in the literature. So
there are particular features on echocardiography that one can
look at to increase the chance of picking up this disease. And in
particular the big increase in the number of diagnoses over
recent years has been because of cardiac MRI scanning, which has
become an increasingly used tool for the investigation of heart
failure in which one gets a very characteristic picture of late
gadolinium enhancement when it's performed in a patient with
cardiac amyloidosis, which immediately triggers people to think,
ah, here it is, we've got amyloid.


                                               
And the other sort of novel diagnostic technique as being bone
scintigraphy. In the UK we use a bone tracer called DPD and in
the US a bone tracer called PYP, and those bone tracers have
exquisite sensitivity for cardiac amyloidosis. So if one injects
these tracers in a patient with cardiac amyloidosis one gets
cardiac uptake into the heart, which can't really be missed on a
planar scan. So those two techniques basically, the increasing
needs of cardiac MRI and the increasing use of bone scintigraphy
to investigate patients with heart failure have resulted in a
great increase in the number of diagnoses.


                                               
The last thing to say is that a huge proportion of patients with
amyloid or transthyretin amyloid cardiomyopathy have actually had
carpal tunnel syndrome previously. The median time from carpal
tunnel syndrome to presentation with heart failure is about seven
years, but that is another red flag, if you like, that ought to
at least trigger a doctor to think could be amyloid. A thick
walled heart in the context of someone whose had previous carpal
tunnel syndrome. So there are a few clues there as to how one
might make an earlier diagnosis, which is absolutely necessary
given the nature of our data, sharing the delays that I outlined
down here.


Dr Greg
Hundley              
And Julian, last quick question before we get with Justin here.
In your data, can you describe for us the importance of that
earlier diagnosis related to long-term outcomes as opposed to the
group that was diagnosed much later, you know, beyond your
median. What was the difference in prognosis in those two groups?


Dr Julian
Gilmore:           
There is no doubt that if patients are diagnosed earlier, they
survived for longer, reflecting the natural history of the
disease. So these patients, as I mentioned earlier, did not
receive any disease modifying therapy and we did divide the
patients into pre 2012, when patients were essentially diagnosed
by endomyocardial biopsy, or the vast majority of them were
diagnosed by endomyocardial biopsy, and post 2012 by which time
most patients were diagnosed via an imaging, if you like,
algorithm that we published in 2016 in the same journal in
circulation. And the patients who were diagnosed earlier had
significantly improved survival. Just corroborating really the
fact that they were actually diagnosed earlier. What's
particularly relevant there, is that the treatments that have
been developed for this condition, and there are some recent new
potential disease modifying treatments that have been developed,
they find that things seem to slow progression of the disease
rather than stop it or reverse it, so that if one can diagnose a
patient early when their quality of life is still good and then
slow progression, there's a high chance of improving quality of
life quite substantially and obviously prolonging life.


Dr Greg
Hundley              
Thank you so much, Julian. And Justin as the managing editor of
this article, what struck you most in terms of its results and
conclusions, and how we should manage patients today suspected of
transthyretin amyloid?


Dr Justin
Grodin:             
Well, I would say that really there are four things that in my
opinion that were quite striking. The first at least as
highlighted by Professor Gilmore is that the UK National Amyloid
Center, they get the national case load. So this is unlike other
cohorts and other centers across the world in that this is
subject to less referral bias than others. So I think that's the
first thing that's quite impressive. And I think Professor
Gilmore really hit the nail on the head when he highlighted that
this paper, that this analysis really underscores the importance
of an early efficient diagnosis. And a lot of this is really
through his seminal work in achieving a non-biopsy diagnosis of
ATTR amyloidosis and his findings have been replicated in other
cohorts as well. So I think those, I would like to say are really
one and two.


                                               
And then number three, which is one that I don't think Dr Gillmor
mentioned, I think he mentioned indirectly, but we were also
struck by the prognostic importance or I should say the
prognostic meaning of having the V122I mutation. So these are
individuals like hereditary amyloidosis and they have a single
mutation. This is the one that is prevalent, at least we think
from population studies, in approximately 4% of the African or
Afro-Caribbean population. And we really see unequivocally that
the time from symptom onset to diagnosis was shorter and the
prognosis was actually worse in comparison to other mutations or
in individuals with wild-type amyloid. And this is an important
finding really for two reasons. Number one, it is largely
confirmatory from other studies, but it's important to note that
those studies were subject to referral bias. And we could never
ever successfully incorporate whether or not socioeconomic status
had actually influenced the bad outcomes of these individuals.


                                               
And I would say that Professor Gilmore's findings are quite
compelling in that regard. And then the second thing for this
point is really this underscores I think the importance of
genetic testing. I mean I think all the readers can take that
message away. And then the fourth thing, which as Professor
Gilmore alluded was the striking amounts of healthcare
utilization, although it was in a minority, certainly quite
compelling and really what it speaks to is multiple missed
opportunities. Even in the UK where they have a centralized
center of excellence, just like Professor Gilmore's, that there
were delays in diagnosis and then when delayed these patients are
quite ill. And I think I'm making all these points because at
least in 2019, the regulatory environment about amyloidosis,
specifically ATTR therapies. In The United States, it's actually
changed. So a disease where we had therapies that might be off
label or our therapies were largely symptomatic, where we managed
the patient's signs and symptoms, we now actually have disease
modifying therapies.


                                               
So, in the United States in 2018, there were two biological
agents that actually silence the livers production of
transthyretin or TTR and they were approved for hereditary ATTR
polyneuropathy. But there is some suggestion from sub-studies
that those will have the efficacy in cardiac amyloid. And then
number two in the United States, we recently gained approval in
May of a drug that actually stabilizes the transthyretin protein
or tetramer. So in other words, just as Professor Gilmore had
highlighted at the beginning of this call, it stabilizes the
breaking up, if you will, of this protein, which is the rate
limiting step of amyloid formation. So you take this pill and
then the transthyretin molecule does not then deposit amyloid. So
this is really exciting because professor Gilmore's cohort study
really captures now at least the impact that these therapies
might have, and in the United States and across the world and in
the UK, these therapies are being studied for all types of ATTR
amyloid and really they're on the horizon. So it's given us very
deep insights into how these might impact our patient's lives
with ATTR.


Dr Greg
Hundley              
Julian, Justin, that was just such an impressive discussion of a
very important topic and something that again, with
echocardiography, we really need to start thinking about when
perhaps we appreciate some LVH, diastolic dysfunction. We have
apical sparing of systolic function, but abnormal basal systolic
function. Could you just summarize one point, each of you, that
we should be thinking about as we move forward and we're seeing
patients in our clinic that might have this disorder.


Dr Justin
Grodin:             
The first thing to say is that awareness is all important. You
know, 25% of male individuals in autopsy studies over the age of
80 have ATTR amyloid deposits in their heart, and when one sees a
thick walled heart in any situation, and particularly in an
elderly individual, one needs to think, could this be, amyloid,
that's the first thing. And the second thing I'd like to say is
that if that thought occurs, which it should occur at a much
earlier stage than it does probably in most cardiologists minds,
then one should think about either a bone scan, which is a cheap,
simple tests. The PYP scan in the US or DPD scan in the UK and or
an MRI scan, which has a very characteristic picture in a patient
with cardiac amyloidosis. So those would be my take home messages
to try and improve early diagnosis.


                                               
You know, I'd like to dovetail what Professor Gilmore had said
cause he just about took the words out of my mouth and I would
like to emphasize the first point in that the diagnosis of AL, we
mentioned earlier, or an ATTR amyloidosis, really necessitates a
very, very high index of suspicion. What do I mean by that? When
somebody has a thick heart muscle and it's not explained by
something else, in other words, they don't have a lifetime
history of high blood pressure and they don't have high blood
pressure seeing you, or maybe they don't respond adequately to
standard heart failure therapies when something is not fitting,
it's always incumbent to the treating clinician to think amyloid.


                                               
I would also like to highlight some of the clues that Professor
Gilmore had mentioned, that any individual with carpal tunnel
syndrome or who might be hospitalized with heart failure, in
other words, they have shortness of breath and swelling, and the
squeeze of their heart is normal, or the ejection fraction is
normal, that should increase your index of suspicion for
amyloidosis. And then individuals that might've had lumbar canal
surgery or really any issue impacting their tendons. And then
they're now presenting with a thick heart muscle. That should be
a clue. It doesn't necessarily mean it's diagnostic. In fact, the
majority of those individuals might not have, or a large
proportion, might not have ATTR amyloid, but it should certainly
raise an eyebrow and then kind of allow the clinician to move
forward with the evaluations that Professor Gilmore had
mentioned.


Dr Greg
Hundley              
Well, listeners, what a phenomenal discussion that we've had from
Professor Julian Gilmore from London, and Dr Justin Grodin from
Dallas, Texas, educating us on transthyretin amyloid and thinking
about that early and being suspicious as we evaluate patients,
particularly older individuals that are symptomatic with heart
failure. Well, on behalf of Carolyn Lam, this is Greg Hundley. We
look forward to seeing you next week. Have a great week.


Dr Carolyn
Lam                 
This program is copyright American Heart Association 2019