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October 22, 2025

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01:23Yeah.
03:08It's, like, a lot harder
03:09for it than for any
03:11other.
03:12Right?
03:30It's
03:37a
04:38Yeah. Okay. Welcome, everybody.
04:42We'll just get started.
04:43Here's a CME
04:45code.
04:47K.
04:48Just the upcoming schedule for
04:50the next couple weeks.
04:52You can see next week
04:53is doctor Pelletier,
04:55doctor Petrie from the UK.
04:57And we'll have another EP
04:59clinical case conference.
05:01And then upcoming in later
05:03in November
05:04is,
05:05Todd Valenis, which is our,
05:08imaging symposium that same day.
05:10That will be in the
05:10Park Auditorium.
05:12Just a note there. And
05:13then the Zarratt lecture as
05:14well.
05:19Okay. So I'll start off
05:20today by introducing our dynamic
05:22duo,
05:23doctor Gallegos and doctor Abu
05:25Alawi.
05:26So it's my pleasure to
05:27introduce doctor Sarah Abu Alawi,
05:29a third year fellow here
05:30at Yale.
05:32She earned her medical degree
05:33with honors from the American
05:34University of Beirut where she
05:36was inducted into the AOA
05:38Honor Medical Society and received
05:40the prestigious Penro Penrose Award
05:42for excellence in scholarship, leadership,
05:44and contributions to university life.
05:47Following medical school, she pursued
05:50postdoctoral research
05:52at Dana Farber Cancer Institute
05:54at the Harvard Medical School,
05:56where she focused on epigenetic
05:57landscape of genitourinary
05:59cancers. Her research contributions have
06:01been recognized
06:03in leading publications
06:05in nature communication,
06:06cell cancer, and circulation.
06:08She then completed her internal
06:10residency
06:11at Brigham and Women's where
06:13she also served as chief
06:14medical resident.
06:15She has received multiple teaching
06:17and clinical excellence awards.
06:19Currently now as a cardiology
06:21fellow here at Yale, her
06:23training has focused on advanced
06:24imaging and genetics with a
06:25special interest in inherited cardiomyopathies.
06:29Her research to the Yale
06:30card cards data science lab
06:32leverages machine learning and AI
06:34to integrate genetics and imaging
06:36for improved risk stratification,
06:38outcome prediction, and personalized therapy
06:41in patients with cardiomyopathies.
06:43In addition to her research
06:44and clinical work, she is
06:45an active member of the
06:47Yale Women in Cardiology Group
06:48and has been recognized as
06:50the consultant of the month
06:51by Yale's emergency medicine department.
06:55Now her mentor, doctor Cecilia
06:57Gallegos, is an assistant professor
06:59of medicine.
07:00She graduated summa cum laude
07:01from the Universidad National, Ajitama
07:04de Honduras, where she endured
07:06and and earned her medical
07:07degree.
07:08She then completed residency and
07:09chief residency at the University
07:11of Miami Miller School of
07:13Medicine.
07:14Her academic pursuits brought her
07:15to Yale, where she completed
07:17general and advanced cardiology special
07:19fellowships
07:20with specialization
07:21in advanced cardiac imaging and
07:23infiltrative cardiomyopathies.
07:26She's also served as chief
07:27fellow.
07:28During her training, she was
07:29awarded a master's in health
07:31science degree from the Yale
07:32School of Medicine
07:33with a thesis focused on
07:34PET tracers and diagnosis of
07:34angiographic stenosis. Her work resulted
07:36in co
07:38directs
07:40the
07:42Yale
07:44cardiac
07:45amyloidosis
07:47program
07:49programs and co directs the
07:51Yale cardiac amyloidosis program where
07:53she leads multiple clinical trials.
07:55Her current area of research
07:57is in transtheretin stability and
07:59microvascular
08:00dysfunction in amyloidosis.
08:02Outside of her clinical and
08:04research interests, doctor Glaios has
08:05a lifelong passion for medical
08:07education and teaching and serves
08:09as a program director for
08:10the cardiology
08:12cardiology imaging specialist fellowship and
08:14and the associate program director
08:16for the general cardiology fellow
08:17as well. Now please join
08:19me in welcoming doctor Sarah
08:21Abu Alawi.
08:29Good afternoon, everyone. Thank you,
08:30doctor Clark, for the kind
08:31introduction and everyone for being
08:33here.
08:34So
08:35my title, the title of
08:36my talk today is Beyond
08:37Imaging and Cardiac Amyloidosis.
08:40And as many of you
08:41know, cardiac amyloidosis has historically
08:43been considered a rare and
08:45a late stage diagnosis,
08:47one that often becomes apparent
08:49only when imaging findings are
08:51unmistakable.
08:52But over the past decade
08:53or so, our understanding of
08:55amyloid biology and detection has
08:57dramatically transformed.
08:59And in this talk, I
09:00hope to explore emerging biomarkers,
09:02molecular tracers, and AI driven
09:04tools that may allow us
09:05to identify
09:07and risk stratify patients long
09:08before traditional imaging does with
09:11the goal of moving from
09:12detection
09:13to prediction and ultimately prevention
09:15of amyloid cardiomyopathy.
09:18This is our disclosures.
09:22So for the objectives of
09:23today's session, first, we'll briefly
09:26describe the pathophysiology
09:27and the clinical presentation of
09:29inherited transthyretin
09:30cardiac amyloidosis
09:32focusing on whose specific variants
09:34influence disease phenotype.
09:36Then we will illustrate the
09:37natural progression and transthyretin
09:40cardiac amyloidosis from early molecular
09:42dies the from early molecular
09:44misfolding
09:45to avert cardiac involvement.
09:48And finally,
09:49we will discuss the limitation
09:51of current imaging tools and
09:53explore how emerging biomarkers
09:55allow us to detect disease
09:56earlier even before traditional imaging
09:59becomes positive.
10:01So with that, let's introduce
10:03our case,
10:04which is the case of
10:05a sixty eight year old
10:07woman who presented to clinic
10:09after being found to have
10:10a pathogenic transthyretin
10:12variant, which was identified through
10:14cascade genetic testing after one
10:16of her sons was diagnosed
10:18with sarcomereic hypertrophic cardiomyopathy.
10:21So she comes to your
10:22amyloid clinic entirely asymptomatic
10:24yet very concerned about her
10:26abnormal genetic test results.
10:28And her case raises the
10:30key question that will frame
10:31today's talk. How do we
10:33care for someone in whom
10:34the gene speaks first
10:36before the phenotype, before the
10:38imaging, and before the disease
10:40declares itself?
10:42So these are the the
10:43results of her genetic testing.
10:44As you can see, she
10:45has a heterozygous,
10:47variant in TTR gene, which
10:50is specifically the val one
10:51forty two isoleucine,
10:53also referred to as the
10:54val one twenty two isoleucine,
10:55which I will refer to
10:57interchangeably.
10:58And it's a relatively common
11:00variant in individuals of African
11:02ancestry and known to increase
11:03the risk of developing late
11:05onset cardiac amyloidosis.
11:08This schematic shows the entirety
11:11of the TTR coding regions
11:12along with some of the
11:13variants that have been described,
11:15and more than one thirty
11:16trans thylethan variants have been
11:18described to date, each mostly
11:20and by and large representing
11:21a single amino acid substitution
11:24that can alter the stability
11:25of the tetramer in unique
11:27ways. And what's really remarkable
11:29is how specific
11:30substitutions tend to cluster with
11:33distinct clinical phenotypes,
11:34some primarily neuropathics,
11:36other predominantly cardiac, and even
11:38some others being protective.
11:41Let's focus a little bit
11:43on some of the TTR
11:44variants that are well defined
11:46and are rather common.
11:48So on the right hand
11:50side over here is the
11:51val one twenty two isoleucine,
11:52which is a variant that
11:53our patient has. And it's
11:55estimated to be prevalent in
11:57about three to four percent
11:58of African American individuals.
12:00Typically, it is late onset.
12:02It's predominantly cardiac,
12:04with an estimated up to
12:06a hundred percent penetrance in
12:07patients over the age of
12:08sixty five
12:09and usually affecting more males
12:11than females.
12:12Other well described variants include
12:14the val thirty MET, which
12:16is overall the most common
12:18worldwide.
12:19It actually presents in an
12:21endemic form in Sweden and
12:22Portugal,
12:24and presents mostly with an
12:25early onset neuropathic phenotype, but
12:28can also present in non
12:29endemic regions with a mixed
12:31cardiac and neuropathic phenotype.
12:34And then also the threonine
12:35sixty ala, which is prevalent
12:37in about one percent in
12:38the County Donegal in the
12:39Republic of Ireland,
12:41with an age of onset
12:42typically after fifty and also
12:44a mixed cardiac and neurologic
12:46phenotype.
12:49And so with that, I
12:50also wanna highlight some other
12:51protective TTR variants, which are
12:53rare but actually modulate disease
12:56risk in carriers of amyloidogenic
12:58TTR mutations.
13:00So they actually lead to
13:01delayed onset,
13:02lower penetrance, and milder phenotype.
13:05And we think this happens
13:06because of increased tetramer stability
13:08and also slower monomer misfolding.
13:11And the clinical relevance of
13:12this is, one, typically in
13:14compound heterozygous, say, for example,
13:16like a val thirty MET
13:18with three anine one nineteen
13:20MET, those people actually have
13:22less frequent surveillance. And, also,
13:24this is relevant in terms
13:25of therapeutics. So, for example,
13:27one of the TTR stabilizers,
13:29Akaramidus,
13:30was actually based on these
13:32variants.
13:34And so with that, now
13:36that we have an abnormal
13:38like, now that we have
13:39a mutation, how does a
13:41single amino acid substitution cause
13:44such a different clinical syndrome?
13:46Well, it all comes down
13:47to how these mutations affect
13:49transthyretin stability and folding. So
13:51transthyretin, the protein, which is
13:53also known as pre albumin,
13:55is predominantly produced in the
13:57liver, but also in the
13:58choroid plexus and the retinal
13:59pigment epithelium.
14:03And under normal condition, TTR
14:05circulates as a tetramer, and
14:06it transports thyroxine and retinal
14:08binding protein.
14:10But in both wild type
14:11and variant forms, the instability
14:13of the tetramer leads to
14:14misfolding through two major mechanisms.
14:17The first mechanism is the
14:18dissociation pathway where the tetramer
14:20becomes a dimer, the dimer
14:22a monomer, and then eventually
14:23a misfolded amyloidogenic
14:25monomers
14:26that cause these amyloid tapirals
14:28that we see on the
14:29right.
14:29And then the other pathway
14:31is the proteolytic
14:32cleavage pathway where TTR undergoes
14:34a partial cleavage producing truncated
14:36fragments that are highly amyloidogenic.
14:39And in both these cases,
14:40the amyloid fibrils
14:42deposit inside
14:43the myocardium
14:45and cause what we know
14:46as frank
14:47cardiac amyloidosis.
14:49And it is important to
14:50know that while sometimes on
14:51echo for patients of suspected
14:53cardiac amyloid, we use the
14:54word mild concentric hypertrophy.
14:56The myocytes are really not
14:57hypertrophied. In fact, the amyloid
14:59is in between the myocytes.
15:01And then the second thing
15:02that I should highlight is
15:03something that we call the
15:04seeding phenotype where amyloid begets
15:06amyloid. So, ideally, in order
15:08to prevent amyloidosis, you wanna
15:10prevent it from depositing first
15:12because the more amyloid you
15:13have, the more amyloid is
15:14gonna build up.
15:16And in terms of the
15:17natural history and as I
15:19mentioned,
15:20there are two types of
15:22cardiac amyloid, both the wild
15:23type and the inherited. But
15:24for the purposes of this
15:25talk, we're gonna predominantly focus
15:27on inherited cardiomyopathy.
15:29And, usually, these patients, for
15:31some time, are asymptomatic
15:33carriers until at some point
15:34develop what we call early
15:36stage hereditary cardiac amyloidosis where
15:38we start seeing evidence of
15:39decline in GFR,
15:40increase in their NT proBNP
15:42and troponin.
15:43And after that, we start
15:45seeing more increased heart failure
15:46hospitalizations
15:47and eventually death.
15:49But what I wanna point
15:50out is in this asymptomatic
15:52carrier stage, when the patients
15:54actually have disease and how
15:56can we predict that?
15:58And so there's the concept
15:59of predicted age of disease
16:01onset in patients with a
16:03TTR variant.
16:04And that stage moving from
16:06asymptomatic TTR variant carrier to
16:08at risk asymptomatic
16:10TTR variant is really crucial
16:12because it will influence a
16:14personalized surveillance strategy for these
16:16gene carriers.
16:17And this is predominantly affected
16:19by the specific TTR variant
16:21that they have, the typical
16:22age of onset the CTR
16:24variants have in populations,
16:26and also the age of
16:28onset in family members who
16:30have this mutation.
16:34So to shift gears back
16:35to our patient, she's in
16:37clinic. You're taking your history.
16:39She tells you, well, I
16:40have a history of high
16:41blood pressure. I'm on three
16:42blood pressure medications.
16:44She has obesity with a
16:45BMI of thirty five, bilateral
16:47carpal tunnel syndrome, and lumbar
16:49spinal stenosis.
16:50She's had a history of
16:51bilateral carpal tunnel release
16:53as well as fixation of
16:55lumbar stenosis.
16:56She has extensive family history
16:57of hypertrophic cardiomyopathy, which we'll
16:59delve into in a second,
17:02and really has unremarkable
17:04social risk factors
17:05and really nonrelevant
17:07allergies.
17:09And in terms of her
17:10family history, this is a
17:12pedigree that I was able
17:13to compile from the chart.
17:14So our proband,
17:16let me just use the
17:18pointer.
17:19Our Proband, who is right
17:20here, she is a carrier
17:21of this variant,
17:23basically came after her son
17:25was diagnosed,
17:26of HCM in at a
17:29young age and then went
17:30to ultimately receive a heart
17:31transplant here at Yale at
17:33the age of forty.
17:34He was tested and was
17:35found to have
17:36a sarcomereic mutation,
17:38and his son also was
17:40diagnosed with HCM at two
17:41months and had sudden cardiac
17:43death at ten years and
17:44eventually also went to have
17:46a heart transplant
17:47at fourteen year old.
17:49Now in terms of our
17:50patient's maternal history,
17:52we know that she has
17:53this unclear history of cardiomyopathy
17:56in both her mom and
17:57her maternal aunt, but really
17:59unclear what's going on there.
18:01And then the father here
18:03has an extensive family history
18:04of HCM and we think
18:06sent the HCM gene down
18:08to his sons. Her daughter
18:09and her granddaughter were both
18:11free of disease.
18:14On exam, her vital signs
18:15are pretty much unremarkable.
18:18Her exam is also
18:19unremarkable with no signs or
18:21symptoms of heart failure
18:23and no evidence of any,
18:25pathognomonic,
18:26amyloidosis
18:27signs.
18:29So what do the guidelines
18:30tell us? You know, how
18:31are we gonna proceed to
18:32diagnosing her with so called
18:34cardiac amyloidosis?
18:36Well, first, we're gonna go
18:37ahead and get our history,
18:39our EKG, our echo, and
18:40our cardiac MRI. We're gonna
18:42make sure she has no
18:43AL amyloid doses based on
18:45SBAP with immunofixation
18:47and serum free light chains,
18:49and that's kind of the
18:50pathway over here, which is
18:52not the focus of our
18:53talk. And if all of
18:54this workup is negative for
18:56AL amyloidosis, then we're gonna
18:58proceed to get a PYP
18:59or HDMP or any other
19:02cardio cardiac radionuclide imaging.
19:05And if that is negative,
19:06then by the guidelines, this
19:08is unlikely to have cardiac
19:09amyloid. And if it's positive,
19:11then we proceed to genetic
19:12testing.
19:14And this is exactly what
19:15we did. Her labs were
19:17pretty unremarkable, so n t
19:18proBNP was below assay. High
19:20High sensitivity troponin, very unlikely,
19:22but really is nine. Pre
19:24albumin, which is again the
19:26t t r, is seventeen
19:27point eight. She had a
19:28normal creatinine, and her AL
19:30labs were normal.
19:32She also had an EKG
19:34which showed sinus rhythm with
19:35a prolonged PR interval
19:37and a borderline left axis
19:39deviation.
19:41She had an echocardiogram
19:43which showed, again, increased LV
19:46wall thickness with an estimated
19:47interventricular
19:48septum thickness of about one
19:50point two centimeters.
19:52She had
19:53normal preserved left ventricular and
19:55right ventricular systolic function, some
19:57mild MR,
19:59but really nothing otherwise significant
20:01and no pericardial effusion.
20:03Strain was not performed on
20:05the echo, and this was
20:06performed at an outside hospital.
20:09She also had,
20:11a technician ninety nine m
20:13HMDP
20:13study,
20:15which was negative.
20:16Basically,
20:17the visual or the three
20:19hour visual uptake score was
20:20zero. As you can see
20:21here, there's no heart on
20:23the
20:24red.
20:26And she had a nuclear
20:27SPECT as well, which was
20:28negative. And the way I
20:30see this for people who
20:31don't look at this a
20:32lot, if you see a
20:33heart, it's a bad thing.
20:34If you don't see a
20:35heart, it's a good thing.
20:37And the fact that we
20:38don't see a heart means
20:39that there was no myocardial
20:40uptake.
20:42She also had a cardiac
20:43MRI,
20:45which basically was read as
20:48no evidence of cardiac amyloidosis.
20:50She had normal right right
20:51and left ventricular size and
20:53function. She had no left
20:54ventricular gadolinium enhancement, and the
20:57images are on this bottom
20:59right side. This is one
21:00representative
21:00image.
21:01This is a t one
21:02scout images which basically showed
21:04a normal, quote, unquote, nulling
21:06pattern. She had mild by
21:07atrial enlargement, normal t maps,
21:09and the ECV was not
21:10described.
21:12So let's put her together.
21:14This is a sixty eight
21:15year old woman with a
21:17val one twenty two isoleucine
21:18TTR variant and no clinical
21:20evidence of infiltrative cardiac disease
21:22based on lab and imaging
21:24data. And I know some
21:25of you may bring up
21:27the increased LV wall thickness,
21:28but she was also hypertensive
21:30on three blood pressure medications
21:32with
21:33normal imaging.
21:34And so, she was defined
21:36as a patient with preclinical
21:37disease.
21:40So let's look at our
21:41diagnostic tests of ATTR amyloidosis
21:44and how are we doing.
21:45Well, echo, great. It's loose
21:47for diagnostics and sometimes also
21:49for therapeutic surveillance.
21:51We mostly care about the
21:52global longitudinal strain, the wall
21:54thickness, the diastolic function.
21:57We also
21:58are happy because it's widely
22:00available with no ionizing radiation
22:02and pretty rather short duration.
22:03But the principal limitation are
22:05mostly body habitus of the
22:06patient, limited tissue characterization,
22:09and it's really nonspecific
22:10in determining amyloid from anything
22:12else.
22:13In terms of CMR,
22:15it's really mostly used for
22:17prognostic,
22:20from a prognostic importance.
22:22Usually, we look at the
22:23late gadolinium enhancement pattern, the
22:24nulling pattern, the extracellular
22:26volume fraction, and the native
22:28myocardial t one time. It
22:30is also,
22:32offered with no ionizing radiation,
22:34the function and the tissue
22:35characterization and grade, and it
22:37does exclude alternative etiologies.
22:39But it does need center
22:41expertise. It's dependent on patient
22:43factors and really,
22:44does not have much multicenter
22:46study data.
22:47And finally, in terms of
22:48radionuclide
22:49imaging,
22:50we do need SPECT or
22:51SPECT CT.
22:54It excludes plasma cell disorder,
22:55and it's widely available. It
22:57has minimal radiation exposure but
22:59with long trace of incubation
23:00time and also has false
23:02positive scans.
23:03And in terms of the
23:05limitations of radionuclide imaging in
23:07cardiac amyloid per se, and
23:10while it has become a
23:11cornerstone for diagnosing tristhyridine
23:13cardiac amyloidosis,
23:15its sensitivity
23:16really depends on disease burden.
23:18So really uptake can be
23:19negative,
23:20in early stage disease. Also,
23:22certain genetic mutations like the
23:24val fifty MET and
23:25the phenyl phenyl sixty four
23:27leucine are also associated with
23:29false negatives because of a
23:30distinct amyloid fibril composition.
23:33And in addition, as we've
23:34learned over the past few
23:35years, planar imaging alone can
23:37overestimate
23:38cardiac involvement. So we do
23:39need SPECT or SPECT CT
23:41imaging.
23:44And with that, you know,
23:45I did ask
23:47Chachibuty and Open Evidence, our,
23:49biggest resources, to tell me
23:51what to do with this
23:51patient. And in concordance with
23:53the guidelines, they say that
23:55there's no disease modifying therapy
23:57indicated
23:58at this point.
24:00Yeah. But let me all
24:01ask you this. This is
24:03a sixty eight year old
24:04patient. She has a disease
24:06causing variant. She already has
24:07carpal tunnel and lumbar spinal
24:09stenosis and maybe
24:10increased LV wall thickness. And
24:12despite
24:13negative imaging and workup, we're
24:15really offering her surveillance.
24:18And I think that question
24:19just gets us to pause
24:20and really think of how
24:22we manage asymptomatic TTR variant
24:24carriers.
24:25Really, the management has been
24:27focused on defining the variant,
24:29the age of onset,
24:31really looking at the history
24:32and the physical exam and
24:33whether they have any signs
24:35and symptoms of cardiac amyloidosis,
24:38directed clinical testing as a
24:40baseline and also as surveillance,
24:42and then frequency based on
24:44symptoms. So we're really gonna
24:46wait for her to declare
24:47herself and then treat her.
24:51And, again, this slide summarizes
24:54how we currently assess progression.
24:56We track downstream effects. We
24:58track NT proBNP, troponin, renal
25:00function, and strain, or we
25:02quantify burden based on radionuclide
25:04imaging or CMR. And I
25:06wanna mention that radionuclide
25:08imaging is really not the
25:09modality to assess amyloid burden.
25:12But, again, let's reflect on
25:13this paradigm because everything here
25:15represents disease after amyloid deposited.
25:19So what if we shift
25:20our focus a little bit
25:21earlier before wall thickening,
25:23before elevated biomarkers to the
25:25asymptomatic
25:26predeposition
25:27phase where fibrils are just
25:29beginning to form? And that's
25:31exactly where the field is
25:32heading, from treating end stage
25:34manifestations
25:35to detecting and intervening during
25:37amyloid formation itself,
25:39preventing clinical disease rather than
25:41reacting to it.
25:44And this is what the
25:45next few slides will explore.
25:46We're gonna explore how blood
25:47based biomarkers,
25:49imaging, and new tracers as
25:51well as emerging AI tools
25:53may allow us to identify
25:54amyloidosis
25:55before
25:56it even declares itself clinically.
26:00So let's talk about biomarkers,
26:02and this is for my,
26:05basic science fans.
26:08The first assay is measuring
26:10actual tranacyridine
26:11concentration or measuring prealbumin
26:13concentration.
26:14And this is basically uses
26:17an immunoturbidometric
26:18method
26:19where you just, you know,
26:20basically combine polyclonal
26:22antibodies with a patient's serum.
26:25Antigen antibody complexes form and
26:27it increases turbidity. And it
26:29basically only binds to the
26:31tetramer and not to the
26:32monomer forms, and then the
26:34turbidity is detected photometrically.
26:36And because this reflects the
26:38total pool of circulating tetrameric
26:40TTR,
26:41it's been proposed as an
26:42indirect marker of tetramer stability.
26:45So we're assuming that the
26:47concentration
26:48equals stability.
26:50And in both hereditary and
26:51wild type ATTR, the pathogenic
26:54misfolding process
26:55eventually leads to lower plasma
26:57TTR concentrations,
26:59and that is thought to
27:00reflect ongoing tetramer dissociation and
27:03catabolism.
27:04And in fact, some studies
27:05have shown that the lower
27:06the plasma TTR is, that
27:08was associated with about one
27:10point five to one point
27:11six fold increase in actual
27:13incident heart failure.
27:16But I do wanna caution
27:17folks that interpreting this assay
27:19is quite tricky because TTR
27:21itself is a negative acute
27:23phase reactant, and it does
27:24fall with inflammation,
27:26malnutrition,
27:27liver disease, and renal wasting.
27:29So low levels are not
27:30always specific for amyloid and
27:32should be interpreted in the
27:33right clinical context.
27:36The second assay that was
27:38developed
27:39is transthyretin
27:41unfolding,
27:42and this is a new
27:43class of assay that actually
27:44detects non native or misfolded
27:47transthyretin
27:48rather than total circulating TTR.
27:50So once the tetramer dissociate
27:52into monomers,
27:54these monomers can unfold and
27:55nucleate into small aggregates.
27:58That's the early step in
27:59amyloidogenesis
28:00as we had talked about.
28:01So this
28:02NNTTR
28:04assay,
28:05it uses a sandwich ELISA
28:07configuration where capture and detection
28:09antibodies are specific to epitopes
28:11that are only exposed in
28:12non native TTR confirmation.
28:15And this makes it highly
28:16specific for detecting misfolded tetramer
28:19fragments
28:20that circulate before fibro deposition.
28:24And in blinded testing,
28:25the actual assay was able
28:27to separate symptomatic
28:29val thirty met familial amyloid
28:31polyneuropathy from healthy controls and
28:32was able to
28:36carriers. And I'll point out
28:38to this, but, basically, you
28:39can see here in red
28:40the presymptomatic
28:42carriers
28:43and in green, the symptomatic
28:45untreated
28:46versus in age matched control,
28:47it's nearly nil. And so
28:49that's, again, one step into
28:51detecting preclinical disease.
28:53The only issue with this
28:54is that it was not
28:55really able to detect the
28:57TTR cardiomyopathic
29:00variant,
29:01but rather the polyneuropathy.
29:03But from a conceptual status,
29:05I think this is the
29:06type of assays that we
29:07are looking for, and this
29:09is a mechanism linked biomarker.
29:13And then finally, a third
29:15assay that I'm gonna talk
29:16about is measuring transthyretin
29:18aggregates or the TAD one
29:19detector. And this was developed
29:21out of the Silesis lab
29:23at UT Southwestern.
29:25This is a structure based
29:28floral
29:29fluorescent probe that was designed
29:31to bind to pathogenic TTR
29:33aggregates, the large beta sheet
29:36rich species that form downstream
29:38of tetramer dissociation.
29:40And using segments of the
29:42TTR
29:43known to drive aggregation,
29:45researchers engineered the STAT one
29:46probe
29:47that would recognize the episodes
29:49that are exposed only in
29:51amyloidogenic
29:52conformations and not in the
29:53native tetramers.
29:54And then they went ahead
29:56and, again, this is kind
29:57of explaining the whole assay
29:59where in amyloidosis
30:00patients, it binds and then
30:02it has a fluorescence with
30:04it that is able to
30:05be detected.
30:06And then they went ahead
30:07and did validation studies from
30:09the Cleveland Clinic and from
30:10UT Southwestern and were able
30:11to show that detected aggregates
30:13in plasma from both wild
30:15type and hereditary ATTR patients,
30:17but not in controls
30:19in AL amyloid doses,
30:20were higher. And importantly, in
30:22a subset of patients with
30:24asymptomatic
30:25aggregates,
30:26which is the one here
30:27in pink, they also showed
30:29a higher signal, suggesting that
30:31these aggregates again form before
30:33organ involvement.
30:36So let's shift gears towards
30:38imaging.
30:39What have we done in
30:40that area?
30:42In imaging, several amyloid PET
30:44tracers, which were initially designed
30:46for beta amyloid imaging in
30:47Alzheimer's disease, have now been
30:49repurposed
30:50to image systemic and cardiac
30:51amyloidosis.
30:53And compounds such as
30:56the Pittsburgh
30:57b compound,
30:59the florbidapine,
31:00the florbidapyr,
31:02and the
31:03flutemetamol
31:04are all thiamflavine,
31:07like,
31:08molecules.
31:09And thiamflavine is a classic
31:11histologic dye which binds to
31:13beta sheet fibrils,
31:14and they have these fibril
31:17sheet binding characteristics.
31:19These tracers recognize common structural
31:21motif on amyloid fibrils, most
31:23likely the beta sheet channels,
31:25so their uptake is independent
31:27of the precursors.
31:28And, notably, flutemetamol
31:30can bind to multiple amyloid
31:32binding sites.
31:34On the left bottom hand
31:36side is
31:37evizematide,
31:38which is a novel tracer,
31:40also known as p five
31:41plus fourteen, and this was
31:43developed specifically for systemic amyloid.
31:45And unlike the thioflavin
31:47analogs,
31:48it targets glycosaminoglycans
31:50which decorate amyloid fibrils,
31:52offering potentially a universal and
31:54more organ agnostic marker of
31:56amyloid burden.
31:58And I won't go into
31:59the details of the thioflavin
32:01analogs, analogs, but, essentially, they
32:03have been shown
32:04to bind both the ATTR
32:06and AL.
32:08And
32:09florvedepyr
32:09has shown to also bind
32:11non specifically
32:12in wild type patients as
32:14well.
32:15The compound b Pittsburgh was
32:17also shown in trials
32:19right here,
32:20where it was tested in
32:22a very small patient population.
32:23So six patients with ATTR
32:26and five patients with AL
32:27amyloid, both in preclinical
32:29disease.
32:30And about one third of
32:31the patients visually
32:33were thought to have disease,
32:34one third were deemed by
32:36fifty percent of the reader
32:37to have disease, and one
32:38third were thought to not
32:39have disease. So, again, some
32:41potential about detecting preclinical disease.
32:45But how about evozematide?
32:47And this is basically one
32:49of the most exciting tracers,
32:51I would say, in the
32:52field. And as I said,
32:54it decorates the amyloid fibril.
32:57In a rest in a
32:58recent retrospective
33:00pilot study of twenty five
33:01patients,
33:02seven that are ATTR wild
33:04type,
33:06it was capable of imaging
33:08systemic and cardiac amyloid across
33:10precursor types.
33:12And remarkably,
33:13it was able to detect
33:14cardiac uptake in all seven
33:16patients that are phenotype negative
33:18carriers,
33:19indicating that evozematide
33:21may visualize amyloid deposits before
33:23conventional
33:24radionuclide
33:25imaging.
33:27So this really represents a
33:28major advance,
33:29moving beyond indirect surrogates like
33:32calcium or phosphate binding to
33:34direct molecular visualization
33:36of the amyloid matrix itself.
33:39And, in fact, there's now
33:41the study called REVEAL, which
33:43we are a part of,
33:44which stands for I twenty
33:46I one twenty four evizematide.
33:48It's being tested in a
33:49large trial,
33:51that plans to enroll about
33:53two hundred patients with suspected
33:55cardiac amyloidosis.
33:56So you can't go in
33:58if you have an established
33:59diagnosis of cardiac amyloid. You
34:01get a single dose of
34:03the tracer,
34:04and the primary outcome is
34:05basically the efficacy and the
34:07sensitivity
34:08for the diagnosis of cardiac
34:09amyloidosis,
34:10but it's also looking at
34:11secondary outcomes such as adverse
34:14effects predominantly,
34:15of the tracer as well
34:16as kidney and liver function.
34:19And the goal is to
34:20understand whether
34:23evozematide can serve as a
34:24first line, noninvasive
34:25diagnostic tool for systemic and
34:27cardiac amyloidosis,
34:29potentially transforming how we identify
34:31disease much earlier in the
34:32course.
34:34And let's move a little
34:35bit to artificial intelligence.
34:37So multiple studies have been
34:39done in this space, including
34:40our own,
34:42doctor Aikunumu and doctor Kira,
34:44from the cardiovascular
34:45data science lab,
34:48which was published in the
34:49European Heart Journal this year.
34:51And this study asked essentially
34:53whether AI enabled EKG, so
34:55AI EKG over here, or
34:57AI enabled EKG could detect
34:59preclinical transpiriting cardiomyopathy
35:02before traditional diagnostic imaging.
35:05Using routinely acquired TTE
35:07and EKG images for patients
35:09which were later and eventually
35:11referred for nucleotide
35:12for nuclei nuclei,
35:15amyloid testing,
35:16deep learning models were trained
35:18to recognize subtle structural and
35:20electrical patterns of ATTR cardiomyopathy.
35:23And the key question whether
35:24these AI derived signatures
35:27diverged before overt disease.
35:29Essentially, could we protect predict
35:31ATTR cardiac amyloid two to
35:33three years before it's clinically
35:35recognized?
35:36And this is basically what
35:37they show. In over one
35:39thousand seven hundred patients from
35:41both Yale and Houston Methodist,
35:44They show here that the
35:45AI predicted probability of ATTR
35:48cardiac amyloidosis
35:49is much higher in those
35:51who eventually
35:52progressed to have cardiac amyloid,
35:54and this was even predicted
35:56up to five years prior
35:57to their actual amyloid diagnosis.
36:00They also show that a
36:01double negative screen, meaning AI
36:04is AI EKG is negative
36:05and AI echo is negative,
36:07achieved a ninety percent
36:09sensitivity
36:10effectively ruling out disease, whereas
36:12a double positive screen had
36:14a more than eighty five
36:15percent specificity
36:16identifying those at highest risk.
36:18These results demonstrate that AI
36:20derived EKG and echo phenotypes
36:22can act as dynamic and
36:24scalable biomarkers
36:26for tracking disease progression and
36:27potentially guiding early evaluation
36:30and preventive therapy.
36:32And I actually went and
36:34tested our patient's EKG using
36:36the labs,
36:38both app and web based,
36:41and her probability of ATTR
36:43cardiac amyloid was about fifty
36:44some percent.
36:46So that is a positive
36:47screen,
36:48estimating about three to five
36:50fold higher odds of ATTR
36:52cardiac amyloidosis
36:53compared with AI negative patients.
36:57So let's all come back.
36:58I know I've talked a
36:59lot.
37:00But what does this all
37:01mean for our patient?
37:03Our sixty eight year old
37:04who's just in the office
37:05freaking out about her positive
37:07genetic
37:08testing results. Are we not
37:10gonna offer her anything? Are
37:11we gonna just only serially
37:13evaluate her? Because so far,
37:16none of the
37:17methods that I actually talked
37:19about are clinically available.
37:22So eventually,
37:23this patient actually did have
37:25an option.
37:26She was enrolled in the
37:27ACT Early trial.
37:29And the ACT Early is
37:30a prospective multinational
37:31randomized double blinded placebo controlled
37:34study that will test the
37:36hypothesis that prophylactic
37:38treatment with the next generation
37:39TTR stabilizer, ekoramidis,
37:42in asymptomatic
37:43again, asymptomatic carriers of a
37:45pathogenic TTR variant
37:47can prevent or delay the
37:49development of ATTR cardiac amyloidosis.
37:52Eligible patients
37:54should carry,
37:55a pathogenic TTR variant, should
37:57be within eighteen to seventy
37:58five years of age, and
38:00within ten years of this
38:01concept of predicted age of
38:03diagnosis or PATO.
38:06They will approximately randomize
38:08six hundred patients, at karameter
38:09versus placebo,
38:11and will perform serial cardiac
38:13and neurologic assessments, including
38:15cardiac radionuclide amyloid imaging with
38:18SPECT.
38:19And the primary
38:20efficacy endpoint is signed to
38:22development of ATTR
38:24cardiac
38:25amyloidosis
38:26by basically
38:28cardiac radionuclide imaging. And additional
38:31endpoints also include safety, tolerability,
38:33and effect on cardiac imaging
38:35parameters, serum TTR, nerve conduction,
38:38and neurofilament
38:39light chain.
38:41And what else is available
38:43in the market?
38:44I don't know if folks
38:45have heard about
38:47Nexgrin
38:48zuclamerin.
38:49I think, like, the just
38:51the names here are killing
38:53me. But it's basically a
38:54CRISPR Cas9
38:56gene editing,
38:58based treatments.
39:00And this is probably one
39:01of the most exciting developments
39:02in the field. It's in
39:04vivo
39:05gene editing for transthyretin amyloidosis.
39:07So this approach uses a
39:08CRISPR Cas nine system. So
39:10for folks that are not
39:11really familiar with CRISPR Cas
39:13nine, it is usually delivered
39:15by lipid nanoparticles.
39:16It carries a messenger RNA
39:18for Cas nine and a
39:20guide RNA that is specific
39:21to the t t r
39:22gene. And so once inside
39:24the hepatocytes,
39:25Cas nine would introduce usually
39:26a small frame shift mutation
39:28and that permanently knocks out
39:30the TTR production,
39:32effectively
39:33a one time therapy.
39:35So the first
39:37in human
39:38study was published in twenty
39:40twenty one in New England
39:41Journal of Medicine by Gilmore
39:43et al.
39:44And they looked at, I
39:46believe,
39:47six patients with hereditary ATTR
39:49polyneuropathy.
39:50And after a single infusion,
39:52circulating TTR levels fell by
39:54up to eighty seven percent
39:56within four weeks with no
39:58serious safety events.
40:00Marking the first proof that
40:02CRISPR could be used safely
40:03in vivo.
40:05More recently,
40:06published in twenty twenty four
40:07was a follow-up phase one
40:08study by Fontana et al,
40:10and it extended this approach
40:12to patients with ATTR cardiomyopathy,
40:15both wild type and variant.
40:17They enrolled thirty six participants,
40:19and the mean TTR levels,
40:20as shown here on the
40:21bottom line,
40:23fell by more than ninety
40:24percent and remained suppressed for
40:26over a year
40:27with stable cardio with stable
40:29cardiac biomarkers and NYH class.
40:32Adverse events were generally mild
40:34and mostly limited to transfusion
40:36reactions. And while the trial
40:37reported ninety four percent of
40:39at least one adverse effects,
40:41most of them were actually
40:42amyloid events
40:43and fourteen percent only were
40:45transfusion reactions.
40:47And now
40:49we are, recruiting the phase
40:51three trial or the MAGNITUDE,
40:53which will actually tell us
40:54whether this translates into improved
40:56clinical outcomes.
40:59But overall, it's a remarkable
41:01step towards curative therapy for
41:03amyloid.
41:06And I hope
41:08that now by now, I
41:10was able to illustrate to
41:12you
41:13that what we see in
41:14clinic,
41:15heart failure,
41:17shortness of breath, lower extremity
41:19edema is only the tip
41:20of the iceberg. And in
41:21fact, it's preceded by month,
41:23if not, if not years
41:24of underlying
41:26buildup of amyloid eventually leading
41:28to decompensation.
41:30And this is why we
41:31should totally focus on comprehensive
41:33amyloid care and referral to
41:35amyloid expert centers
41:37with a shameless plug to
41:39our Yale cardiac amyloidosis program
41:41that is led by our
41:42fearless leaders, doctor Gallegos and
41:44doctor Miller,
41:45and that truly,
41:47combines expertise not only across
41:49different fields but also within
41:51the cardiology section itself. This
41:53is the QR code. You
41:54can go into the website.
41:57And, actually, the program now
41:59offers multiple trials
42:01and, also, in
42:02collaboration with the cardiovascular data
42:04science lab, multiple studies for
42:06early detection
42:08and early introduction possibly of
42:10treatment to these patients.
42:12And with that
42:14and to close, I wanna
42:15share a forward looking view
42:18of how we might care
42:19for the TTR variant carriers
42:20in the future,
42:22particularly those who are gene
42:24positive but phenotype, quote, unquote,
42:26negative.
42:27In the future,
42:28a patient with a TTR
42:30variant presenting to you, you
42:32can potentially use an AI
42:33based tool that is based
42:35on genetics,
42:36proteomics,
42:37clinical factors, and predict not
42:40the age of disease onset,
42:41but the age of disease
42:43fibral formation.
42:44And then based off of
42:46that,
42:47then use highly sensitive
42:50imaging and biomarkers
42:52to track disease progression.
42:54And, eventually,
42:55once amyloidogenesis
42:57begins, then we can also
42:58use AI based tools
43:00to select the optimal combination
43:02of therapy,
43:03single therapy, combination therapy, stabilizers,
43:07silencers, or degraders
43:09tailored to the patient's specific
43:11mutation,
43:11organ involvement, and predicted response
43:13profile. And, ultimately, gene repair
43:14therapies,
43:18such as CRISPR
43:19based CTR correction,
43:20could move us from lifelong
43:22management to true prevention
43:24where amyloidosis
43:25never develops at all.
43:27This vision moves us more
43:29from reactive diagnosis to proactive
43:32personalized prevention.
43:35And finally, I would like
43:36to thank multitude and multitude
43:38of people, many of who
43:40are not really shown here,
43:41but have really helped me
43:43become who I am today
43:45and believed in me when
43:46even I didn't believe in
43:47myself.
43:49And, doctor Miller can really
43:50attest, but my path to
43:52being here was never straightforward.
43:54And in fact, we think
43:55we're only ninety five percent
43:57of the way to figuring
43:58out what I'm gonna do.
44:00But kudos to those folks
44:02who really, you know, stuck
44:03with me and helped me
44:04figure it out. And special
44:06thanks to my
44:07family, my husband, my son,
44:10and especially my mom
44:12for accompanying me and being
44:14my anchor in this immigrant
44:16mother physician
44:17journey. So thank you. And,
44:19with that, I'm happy to
44:20take any question.
44:36I'll get started. I get
44:38first steps.
44:39Wonderful presentation.
44:41I'm, of course, incredibly,
44:43biased,
44:44with this topic, but this
44:46was music to my ears.
44:47After my recent tour for,
44:49you know, national international meetings
44:51for AMLO for the last
44:53few months, This is by
44:54far one of the most
44:56beautifully put, comprehensive,
44:58patient centered talks on
45:01early detection
45:02and of preclinical disease and
45:03hereditary TTR.
45:05And we are very excited
45:07that, hopefully, that five percent
45:08that we haven't figured out
45:09yet,
45:10you might want to put
45:11that vision in the TTR
45:14program and, you know, with
45:15all your basic science, work.
45:17This is really incredible, and
45:18I, I think this is
45:20great. So I don't know
45:21if doctor Miller Thank you.
45:23Has
45:25the
45:26incredible
45:28comments.
45:29Sorry, Omar. I saw you.
45:30You raised your hand, but
45:31I thought we can defer
45:32you.
45:37Amazing talk, Sarah. This was
45:39really, really educational. Very, very
45:41helpful.
45:42I have two questions. So
45:43the first one is when
45:44you're showing the the penetrance
45:46of the val one twenty
45:47two,
45:48mutation, it was like a
45:50range of seven to one
45:51hundred percent.
45:52How do we explain that
45:54very broad range, and how
45:55does, like, our pretest knowledge
45:57of the penetrance of each
45:58variant kind of inform
46:01how aggressive we'll be with
46:02this, like, preclinical
46:04Yeah. No, sir. This is
46:05a great question. I think
46:07this is mostly based on
46:08population study and I think
46:10was spread over, like, multiple
46:12years. And so our diagnosis
46:14tools have really changed over
46:15that time, and probably,
46:17you know, the penetrance of
46:18seven percent is not really
46:19accurate. But but who knows?
46:21But I think it also,
46:22as I kinda alluded to,
46:24depends a lot on this
46:26concept of, like, predicted age
46:27of disease onset and, like,
46:29what is the specific variant,
46:32and also, like, age of
46:33onset across the populations and
46:35across the patient's family, a
46:36lot of epigenetic
46:37factors, a lot of environmental
46:39factors.
46:40But the bottom line is
46:41I don't think there's anything
46:42that can tell you exactly
46:44when you're gonna have it,
46:46or if you're actually gonna
46:47have it, but it's a
46:48sort of combination of things.
46:49And that's kind of one
46:50of the areas where, hopefully,
46:51artificial intelligence may also be
46:53helpful.
46:54One more question. So, it
46:56was striking that the double
46:57ELISA assay predicted the neuro
47:00amyloid Mhmm. But you said
47:01not the cardiac amyloid? Yeah.
47:03I think so. This was,
47:04I think, out of the
47:05Jeffreys lab, if if I'm
47:07not mistaken. Mhmm. But, basically,
47:09I think,
47:10for some reason, that is
47:12related to the type of
47:13fibril that is usually, like,
47:15different types of, like, type
47:16a and type b and
47:17Sure. Some of them being
47:19more, like, neuropathic and some
47:20other being cardiomyopathic.
47:22And I think that is
47:22probably related to why the
47:24assay picked up on the
47:25neuropathic,
47:26subtype option.
47:29I'll add my kudos. Really
47:30phenomenal talk, and I agree,
47:32Cessia.
47:33Having been to many,
47:35amyloid talks from the early
47:36days of went to famines,
47:37it was even being developed.
47:39This was exceptionally well done,
47:41so congratulations.
47:43Couple kind of
47:44practical questions. So you mentioned
47:47and you started discussions around
47:48cascade genetic screening.
47:51But can you tell us
47:52what your ideas are and
47:53what we're doing here regarding
47:55cascade
47:56phenotypic screening, I guess, when
47:58you identify
47:59this patient
48:01has lumbar stenosis
48:02and and,
48:03and bilateral carpal tunnel syndrome.
48:05So,
48:07what is our practice
48:09at Yale currently in terms
48:10of making sure those patients
48:12are
48:12not just lost in the
48:14wilderness
48:14and, eventually show up to
48:16cardiology, but maybe phenotypically initially
48:19screened
48:20after that initial diagnosis?
48:22Yeah. No. I think that's
48:23an excellent question. So I
48:24think I'm gonna answer based
48:25on my personal experience. Like,
48:26I think doctor Miller and
48:27doctor g often joke about,
48:29like, every time they're on
48:30surveys, like, at least, like,
48:31all the amyloid patients pop
48:33up.
48:34So I think, like, first
48:35of all, just being aware
48:37of the disease,
48:38being aggressive about screening, and
48:40also being aggressive
48:41not only about, like, stopping
48:43when the radionuclide
48:45imaging is negative, but also
48:47pushing more towards biopsies and
48:48actually making sure that the
48:50patient is not a patient
48:51with cardiac amyloid. That's one.
48:53And I think number two,
48:54with the cardiovascular data science
48:56lab, my impression is that
48:57they're trying to scale this
48:59AI EKG,
49:01tool to actually use it
49:03routinely in clinic where you
49:04are actually able to predict,
49:08the probability of actually having
49:10cardiac amyloid. And I think
49:11that would be something very
49:12cool if it's can be
49:14brought to the clinic and
49:15integrated within our routine use.
49:17Yeah. But, you know, just
49:18to be double that for
49:19great response, but to be
49:20double that advocate,
49:22nobody,
49:24payers
49:25government or nongovernmental
49:26payers are gonna pay
49:28for
49:29tafamidis in a population
49:31that has this screen
49:33with no
49:34outcomes data. So it is
49:37fantastic
49:37to see the panoply of
49:39clinical trials and and great
49:41and I hope you're engaging
49:42in learning how to do
49:43those kind of trials day
49:45to day, like working with
49:46the beaker, so to speak,
49:47two on clinical trials management.
49:49But,
49:50and enrolling those patients early
49:51on is critical. But I'm
49:53I'm curious around
49:54what we do with regards
49:56to symptom.
49:57Yes.
49:59Do you you said they
50:00were asymptomatic,
50:01but how do you define
50:03someone asymptomatic
50:04in this? And and do
50:05you take them through exercise
50:06physiology or CPETs or anything
50:08like that? Yeah. I think,
50:10you know, I'll let doctor
50:11g,
50:12talk more, but I think
50:13that's kind of why this
50:14talk was really kind of
50:16anchored towards really developing better
50:18test novel technology that can
50:20define that asymptomatic,
50:22stage essentially, where it's really
50:25what we define as symptomatic
50:26is really just late onset
50:28cardiac amyloid and kind of
50:29pushing the needle a little
50:30bit further.
50:31Yeah. So to answer the
50:33there's, like, two additional things
50:34that we're doing. In my
50:35fellow time,
50:37doctor Murray and doctor Miller
50:39actually worked on cascade screening
50:40for the New Haven population.
50:42That's why that's how we
50:43identify a subgroup of patients
50:45that have, genotype positive, phenotype,
50:49negative, and they're plugged into
50:50our clinic.
50:51We took that a notch,
50:53up with, do
50:55an educational grant on educating
50:58cascade screening carriers. And, like,
51:00the,
51:01the patients and their family
51:03that, have been identified to
51:04continue to do that in
51:05the community. So that's one
51:07thing.
51:08The second thing in terms
51:09of engaging
51:10those patients, you know, we
51:11know,
51:12with other manifestations of amyloid,
51:14like carpal tunnel. We know,
51:15for example, carpal tunnel happens
51:17about ten to fifteen years
51:19before it heart disease or
51:21amyloidosis becomes apparent. So we've
51:23leveraged that to bring it
51:24to the community. So there's
51:25a lot of relationships that
51:27we have with neurosurgery
51:28and ortho. For example, several
51:31colleagues from ortho,
51:32the time that they're doing
51:33their second carpal tunnel, are
51:35sending the biopsy and sending
51:37the patients to us. So,
51:38then, they're plugged in into
51:40the screening and then it
51:41takes us to your comment
51:43about
51:44are they truly
51:45symptomatic
51:46or not? And which is
51:47an excellent question.
51:50Sometimes we don't know and
51:51that's when CPET becomes,
51:53useful. You know, it's not
51:55that we always use CPET
51:57in particularly
51:58in those that are like
51:59twenty or thirty years,
52:01you know, different from that
52:02predicted age of onset.
52:04And the screening is a
52:05little bit different. For example,
52:06if I have a v
52:07one forty two I genetic
52:09screening that's like thirty versus
52:10someone like the patient who
52:12is like already sixty eight.
52:14So that kind of like
52:16ties into like, you know,
52:17the several questions in like
52:19the penetrance. Because obviously we're
52:20not gonna be doing,
52:22nuclear imaging or radiation patients
52:24that are thirty every, you
52:25know, three years and subjecting
52:27them for a disease that
52:28we know is gonna present
52:29twenty years from then.
52:35So, Sarah, so just,
52:37just congratulations on a wonderful
52:39talk, and I always it's
52:40a really a wonderful thing
52:42when,
52:43somebody,
52:44who's a mentee shows you
52:46things that you,
52:47stimulates new ideas and really
52:49takes the
52:51the the the knowledge to
52:52an to a new level.
52:53So congratulations on that. And,
52:55yeah, I think,
52:57a couple of, you know,
52:58sort of comments in that
52:59space and then a question.
53:00I think it is interesting
53:01to hear your their talk
53:02because when we started this,
53:04the mantra was everybody with
53:06half PEP should get a
53:07PYP or HMDP screen. And
53:09now we're moving that needle
53:10right to a different population
53:12of prevention.
53:14So I think that that's
53:15a that's a fantastic concept
53:16that we need to engender,
53:18across,
53:19all of our domains.
53:20And the second comment is
53:22about
53:23the ACT Early trial. And,
53:25Eric alluded to this, but
53:26think about this trial that
53:28a pharmaceutical company has been
53:30so courageous to support, which
53:32is basically,
53:33a trial that's looking at
53:34asymptomatic patients and treating them
53:36or randomizing them the treatment
53:38with no hope of really
53:40ever having an ROI. Right?
53:42Because that's gonna be the
53:43results from that are gonna
53:44be five years in the
53:46future and those but it's
53:47really a natural history study
53:50of TTR amyloidosis in asymptomatic
53:52gene carriers. So that's it
53:54can be just a phenomenal
53:55study to understand.
53:57And then my last my
53:58question for you really is
53:59incorporating all these all these
54:00concepts of prevention and therapeutics.
54:03How do you see the
54:05cost effectiveness? I know you
54:06didn't talk about this, but,
54:07like so how do you
54:08sort of see some of
54:09the some of those decisions
54:11or some of those modeling,
54:13playing out about the different
54:14therapies and and strategies that
54:16could be employed here?
54:18Well, I I think it's
54:19twofold.
54:20One big, like, disclaimer that
54:22I'm not the cost effective
54:24person in the room. But,
54:26two things. I think one,
54:27using AI is super scalable,
54:29very cheap. And I think
54:30this is demonstrated again and
54:31again that we can use
54:32it everywhere, especially with, like,
54:34the Ecolabs
54:35studies across the continents Mhmm.
54:37Of being it's such a
54:38scalable tool. So I think
54:39from a diagnostic perspective, I
54:41think it's not gonna be
54:42an issue,
54:43especially with the technology being
54:44so available even with single
54:46VP KJ's. And I think
54:48from a, you know,
54:50treatment perspective,
54:51you know, we I've shown
54:53at least, like, two therapies,
54:54but I know that many
54:55and many and many are
54:57being developed. And I think
54:58that competition to, like, who
55:00develops
55:01the better drug is just
55:02gonna open the market for
55:03more and more drugs. And
55:04with more and more drugs
55:05available, I hope that people
55:07will, like, you know, start
55:09lowering the prices so that,
55:11you know, people actually use
55:12their drugs, and that would
55:13be, like, why, you know,
55:15people may tend to that.
55:16So I hope that that
55:17is,
55:18you know, what the future
55:20holds.
55:20Oh, yeah. I guess I
55:21should edit my comments because
55:22this is recorded, and it's
55:24totally gonna have a good
55:24ROI. BridgeBio, it's gonna give
55:26a great ROI.
55:33Sarah, that that was a
55:35very professorial
55:37presentation, so I'll call you
55:39professor at least for this
55:41for this hour.
55:43So, you know, maybe following
55:45up a little bit on
55:46some of the other comments,
55:47I think early
55:49treatment of asymptomatic
55:51individuals
55:52in any disease state
55:54is going to
55:56our our enthusiasm
55:57for that is going to
55:58depend on the risk benefit
56:01ratio,
56:02essentially, or analysis.
56:04And so that kind of
56:05loops me to the CRISPR
56:07Cas9
56:09story where,
56:10you know, gene editing is
56:12potentially curative.
56:13Right?
56:14And
56:15the issue there, I think
56:17the biggest concern with that
56:19kind of gene editing is
56:20specificity
56:21and off target gene off
56:23target effects.
56:24So I'm my question is
56:26in the studies that you
56:27mentioned,
56:29do you know how many
56:30different
56:31genetic variants were tested?
56:34Because it's not one guide
56:35fits all. Right? It's gonna
56:37be different guides for different
56:38targets of the gene
56:40that
56:41are variant.
56:42And some are probably gonna
56:43work very well, be very
56:45specific, have no off target
56:47effects, and some won't be
56:49like that. So it those
56:51published studies, did they test
56:53a bunch of different variants,
56:54or was it did they
56:56focus on
56:57on one? Thank you so
56:58much, doctor Bender. This is
56:59such a great Profession. Coming
57:01from you. But,
57:02I actually don't know the
57:03answer because I mostly looked
57:04at the clinical studies. So
57:05I don't know in the
57:06preclinical setting, like, how many
57:08guides they actually tested on
57:10in animal models and some
57:11ways. But I can definitely
57:12look into that and get
57:12back to them. Okay. Yep.
57:14Fair enough. Actually,
57:16you are I don't know.
57:17I'm done.
57:20Actually, you asked the same
57:21question but not not in
57:23this in that format because,
57:25actually, this is more CRISPR
57:26cast knockout.
57:28So it doesn't matter what
57:29mutation you have. They actually
57:30target the whole gene. Yeah.
57:31So even if you have
57:32variants yeah. This is not
57:33the this is not gonna
57:35be correction of your, variant.
57:37So it it they have
57:38done every different type many
57:40different types. But my question,
57:42obviously, what Jeff mentioned is
57:44obviously a concern that the
57:45off target effect still can
57:47be there.
57:48And that has been kind
57:49of causing problem with other
57:50CRISPRs. I don't know how
57:51much you know about that
57:52in this area.
57:53That was one question. And
57:54the second is that you
57:56mentioned, which is correct, that
57:58we have to always use
57:59light chain
58:00rule out light chain first.
58:02But we often see people
58:03coming from outside hospital with
58:05the PYP scan
58:07positive.
58:08How often are they falsely
58:10positive that this pathway has
58:12to be kind of regarded
58:14and say, okay. You should
58:15have done the first AL,
58:17then come to me as
58:18a cardiac. How often do
58:19you have false positive? Yeah.
58:21So I think that's a
58:22great question, and I think
58:23I personally had that with
58:25many of my patients, so
58:26they actually can be, like,
58:28have both diseases.
58:30The frequency, I don't know
58:31off the top of my
58:32head, but it's not insignificant.
58:34And and the guideline recommendations,
58:36technically
58:37technically speaking, the guideline recommendations
58:39is rule AL out first
58:40Right. Then test for TTR,
58:42but most people do it
58:43simultaneously.
58:45But but I do think
58:45it's important, like, from a
58:47clinical perspective to do I
58:48don't know if you have
58:48an exact number.
58:54Yeah. The the rate of
58:55MGUS, which is what we're
58:57usually concerned about in this
58:58population, is between fifteen and
59:00twenty percent of all patients
59:01who are referred for TTR,
59:02which is which we do
59:05or we're meticulous about tracking
59:07down those results and repeating
59:08them,
59:09and it prompts a lot
59:11of referrals to our hematology
59:13colleagues, and it also,
59:14speaks to the expertise of
59:16our center because we have,
59:19the ability to do to
59:20do, endomyocardial biopsies on native
59:22hearts. And that's a really
59:23key aspect of of our
59:25program to ensure that we're
59:27we're,
59:29maximizing
59:29specificity in those complex patients.
59:33And to answer your second
59:34question, I don't know about
59:36the off target effect.
59:43TTR and, like, crossing the
59:45blood pressure barrier and also
59:47the effect of, like, lowering
59:49the overall TTR
59:50to to transport, you know,
59:52thyroxine and but we don't
59:54know because these, you know,
59:56we probably need to wait,
59:57like, a decade or so
59:58to see, like, those potential
60:00of targets.
01:00:02Perfect. Well, thank you everyone
01:00:04for being here today. I
01:00:05really appreciate it. Thank you.