ATTR Cardiac Amyloidosis

0:14 dr lewinsky i think you're muted still right how are we doing okay there we go okay good morning and thank you uh it's a pleasure to be here it's a pleasure to work with the amyloid support group i thank everybody for joining being an amyloidologist is really a unique experience we've become very very close to our patients close to their families and the ability to communicate and share information with everybody really is the key to what makes everything good for everybody i'm head of nuclear cardiology and head of the amyloid clinic so i'm really actively involved in both the diagnostic process and the management of our patients and

1:00 so as i go through today's presentation i hope to demonstrate the need to raise awareness of the prevalence of attr amyloid increase the amount of appropriate testing and hopefully this will lead to earlier diagnosis earlier treatment better outcomes and better quality of life for our patients so i want to start out with a couple of little vignettes okay this is me in 1983 i had just finished my residency and was about to start my cardiology fellowship it was really a tough time because hiv aids was just being diagnosed in fact i admitted one of the initial

1:46 cases that was submitted to uh cdc that led to the diagnosis it was a very very tough time we had very many sick patients we had patients who were sick and we didn't know what was wrong with them we had patients who we knew what was wrong with them that we didn't know how to treat and we had treatments available that patients couldn't afford but if you look at it now a person living with hiv has a similar life expectancy to an hiv negative person provided they're diagnosed in time have good access to medical care are unable to adhere to their hiv treatment i'd love to be able to say that that's where we are with amyloid but unfortunately this is an example of where we are 76 year old afro-caribbean male with no

2:33 history of diabetes or hypertension had seen his cardiologist for two months prior and told everything was good he had a stress test and he had an echo done that was mildly abnormal function was a little bit decreased but the echo showed moderate thickening of his heart he went to the emergency room complaining of abdominal pain 20 pounds of weight loss short of breath and inability to walk he had a long history of numbness in his hands and toes that was attributed to cervical and lumbar radiculopathy but he got worse and worse was at the point of using a cane and then a walker he showed up in the emergency room and he had some blood tests such as the bnp which is a marker of heart failure a troponin that was a marker of heart injury

3:18 and an echo that showed his heart function or the ejection fraction was decreased to 38 percent all of these were markers for severe disease unfortunately he was told that he had heart failure he was referred to neurology he was referred to gi no testing was done on the etiology of his heart disease he was discharged after 24 hours and he was discharged with nobody in charge of his care and no instructions on what to do so he went to all these sub-specialists he had no answers no tests no diagnosis now for somebody like me who has all of these presentations with ekg changes neuropathy swelling in

4:04 his legs gi symptoms it's very clear what he's got he's got a very very articulate heart and he has amyloidosis unfortunately by the time he presented to me was really too late he was started on uh disease modifying therapy but died within three months of the time that i originally saw him so let's talk about a little where we're going cardiac amyloid it's there all over i have bassett hounds this is fred the bassett who i follow regularly and he's always looking for something that will make things better but if you don't think of looking for it you won't find it but if you find it you can help and that's really what the amyloid support group and the amyloidologist like to do so what is amyloid what are the effects

4:49 on the heart what are other organs involved with amyloid how do we make the diagnosis what are the treatment options and how effective are they and what can you with the patient expect and i think if you're armed with understanding all this you'll be much better off as you interact and your family interacts with your uh clinicians so as we talked about there are two major types of amyloid there's the al or light chain amyloid that we talked about last week and there's a transthyretin amyloid or the attr amyloid which is what we're going to focus on today ttr amyloid is a real disease of proteins gone bad transthyretin

5:35 which is a normal protein that exists made in the liver it carries thyroxine and it carries retinol so the name transthyretin and it's like anakin skywalker it's a good guy we need it to transport thyroid we need it to make sure that the eyes are working properly but it undergoes a change and it becomes darth vader and it turns into these large fibrils that infiltrate a variety of tissues particularly the heart we look at what happens here you can see uh in the liver transthyretin is made and you can see it looks like a four leaf clover okay it's called the tetramer it has four pieces to it that's all connected but what happens

6:21 either by a genetic abnormality or an unusual aging process that this tetramer starts to break apart and then you have what left is called monomers or these individual pieces then that group together form clumps form fibrils that then deposit into the myocardium or into the nerve tissue or into the gi tract or into the eye or into the nervous system that cause a variety of diseases in america atpr amyloid is now the most common form as you can see here the most common type of amyloid is wild type most of these people are males most of these people are of the medicare age population average of 76. the initial

7:07 characteristic was that they have uh a thickened heart the ibs means they have a septum which is the heart muscle and i'll show you in a little bit that's sticking to one and a half times or more than normal their heart muscle functions normally overall and the survival of these people is about 58 at three years hereditary amyloid is seen less commonly in america we see it in different spots one of the places where we see it is in the afro-american population three to four percent of all afro-americans carry the gene for what's called b122i and these patients may develop amyloid this is a disease

7:52 that 50 percent of offspring of a patient who has it will will develop i'm in south florida's we a lot of people who are afro-american afro-caribbean so we really see a large amount of this there are some other genetic abnormalities that trace back to ireland and portugal and these present differently as you can see in the graph on the left that some forms of hereditary attr have predominantly neurologic presentation some such as the b121 have the predominantly cardiac presentation but most people are mixed and if you look over on the right you can see that cardiac involvement and neurologic involvement is present in most

8:39 but not all of these people and about 80 percent of patients have um involvement of both so why do we have so much trouble making a diagnosis of amyloid well part of it is the way we practice medicine now we live in silos the neurologist looks at what he's looking at the cardiologist looks at what he's looking at the gi doctor looks what they're looking at the arrhythmia doctor electrophysiologist looks at their problems nobody really looks beyond their individual scope of expertise or interest but you realize that as you can see up here that we really are all connected and the ability to get the message out that we should be looking for red flags beyond

9:25 our individual scope of expertise and make us think that people have a systemic disease as opposed to a single organ disease will allow us to better make the diagnosis vamolite early on so the question is amyloid a rare disease uh overall the definition of a rare disease is less than 200 000 cases but when you look at the data on ttr amyloid it's found in a quarter of patients over 85 who have an autopsy done patients with heart failure with preserved ejection fraction that's a term you'll hear a lot over the day half path or diastolic dysfunction or heart failure with with with normal

10:11 function have autopsy findings of amyloid pyp imaging which is the standard non-non-invasive test that we use for the diagnosis of amyloid 13 of people who go into the hospital with this type of hepatitis who are imaged are positive for amyloid and one in seven patients who undergo tavr now tavr is the transcatheter procedure to replace the aortic valve that sure many of you have heard from uh that has eliminated the need to do surgery uh on patients who have what's called aortic stenosis one out of seven of these patients staying positive for ttr amyloid so the question is that this is not really a rare disease particularly ttr amyloid as i said it's a disease of the elderly

10:57 primarily and as you see once you get to the age of 80 40 percent of patients are found to have amyloid now we still don't understand is this a different disease when you're 80 than it is in your 60 and 70 what is the natural history of it uh what are the treatments are the treatments that we would recommend in somebody 60 70 or 80 years old the same as what we would recognize age 80 and 85 and 90 people we're beginning to look at some of the natural history at our institution but we don't have that data yet so let's look at the cardiac manifestations of amyloid congestive heart failure atrial fibrillation which is a rapid irregular heartbeat slow heart rate or conduction diseases

11:44 requiring a pacemaker and as the disease advances they develop cardiac failure increased risk of sudden death and what's called cardiorenal syndrome which means the kidneys in the heart don't play well in the sandbox together and as cardiac function decreases renal function decreases and it becomes this uh snowball of worsening uh function quality of life and then death so let's talk a little bit about cardiac function the job of the heart is to pump blood to the organs it's any like any other pump like a pump that you blow up your bicycle tires with has a filling phase called diastole and a squeezing phase called systole heart failure is a situation where the heart does not pump an adequate amount

12:29 of blood or the pressure required to get enough blood pumped out is too high and that backup pressure uh causes a variety of symptoms such as shortness of breath and you can get heart failure from either one if you look on the right you see diastolic dysfunction and what you can look at here is you can see that the heart is thickened and the cavity is really very very small so the heart can only pump what it can fill so for each heartbeat the heart is pumping a lot less than it would otherwise on the other hand heart failure with systolic dysfunction means the heart is dilated it's very full but it can't pump enough blood out to the body so for those of you who are new yorkers

13:16 and remember warner wolf who used to say let's go to the videotape let's go to the microscope and characteristically looking at the pathology you can see these fibrils that are interspersed between the myocytes or heart muscle cells we use typically congo red staining and we can pick these up as large fibers that are infiltrating the tissue in large amounts if we look at through a polarized microscope we can see this typical apple green by refrigerants and these findings are fairly typical and diagnostic of amyloidosis so in a biopsy if we need to do it is a reasonably good way to make a diagnosis the goal however is to make a diagnosis without having to go to myocardial biopsy this is what an amyloid heart looks like

14:02 you see thickening of the left ventricle you see thickening of the right ventricle you see enlargement of what's called the left atrium and enlargement of the right atrium and you see thickening of what's called the intra-atrial septum the leaflets of the mitral valve here become thickened and we can see this all on echocardiography or on uh cardiac mr where they're suggestive but not diagnosed in addition to heart failure we get a variety of electrical abnormalities now the normal cardiac impulse starts up at the sinus node conducts through to the av node and conducts through what's called the bundles you have a left bundle and a right bundle branch block and with amyloid you can have

14:49 infiltration of any of these conducting tissues so that you can develop for the right bundle branch block you can develop left bundle branch block you can totally impair conduction and then the heart will either stop or go very very slow or because this sinus node doesn't work well you can develop what's called atrial fibrillation which is a rhythm where the heart is irregular where the upper chambers don't contribute to contractility the heart doesn't feel well and cardiac output or cardiac delivery decreases let's talk now about some of the non-cardiac symptoms because this is as i said a multi-organ disease and i'm actually going to show you two slides of this because you're going to realize how many different ways that this can present way back when we

15:34 used to call syphilis the great masquerader now i think amyloid is the great masquerader because so many different types of presentations carpal tunnel is one of the most common findings in patients who have amyloidosis patients who have ttr amyloid 50 of patients are found to have a history of carpal tunnel syndrome bilaterally ten percent of patients who have carpal tunnel syndrome turn out they have amyloid if you stain them now this is important because the carpal tunnel syndrome occurs very very early often ten years before cardiac presentation now it doesn't mean that you should be taking everybody with carpal tunnel syndrome and looking for amyloid with that but if you see it in the chart and you see it with somebody's got heart failure

16:19 and somebody who has some of the other symptoms it raises a red flag to make you look for it you can have lumbar spinal stenosis in the spine you can have neuropathy with numbness tingling swelling of the legs often we confuse this disease with diabetic and hypertensive heart disease but the people who have the neuropathy from amyloid and you'll hear a little more about it when you talk to the neurologist it becomes more progressive it goes higher up on the legs and it's uh it's more pronounced people get floaters people get a lot of gi symptoms they get poor appetite constipation diarrhea and picture somebody who can't walk very well and walk very far who has to deal with diarrhea get to the bathroom seven or eight times a day

17:06 it's really very very difficult for these people some of the other things that you see are what's called autonomic dysfunction autonomic dysfunction means the regulatory nerves are not functioning properly normally when you stand up you should be able to increase the blood return to your heart by increasing your heart rate and bringing the blood back but with amyloid you don't have this so the blood pressure tends to fall so you feel weak and dizzy if you already have impaired cardiac function and you can't stand up you tend to sit more and get weaker women tend to get urinary tract infections because they don't void properly and this often may be a sign maybe confused with a diabetic who also may be

17:51 prone to urinary tract infection but urinary retention is a significant finding here sexual dysfunction again the diabetic with heart failure may have it due to vascular abnormality but we also see this in men with amyloid so if they don't respond to drugs like cialis or viagra think about this as abnormalities this disease progresses rapidly much more so than typical plain old heart failure or plain old neuropathy so the fact that somebody may have been really good two three months ago but now comes in really debilitated from multiple organ abnormalities so they have heart failure and they can't walk and they're dizzy when they stand up and they've lost weight should all be red flags and make you think of amyloid so

18:42 it has been hard to make this diagnosis there's no doubt about it if you look at this that was published by the amyloid research consortium in the top graph looked at number of doctors that were seeing in the bottom graph looked at the number of cardiologists we're seeing most people saw two or more cardiologists and most people saw significant numbers of overall physicians um so why has it been such a problem i mentioned the fact that we worked in silos part of the problem though is we had no organized way of diagnosing this disease non-invasively and we had no treatment originally so we didn't really look for the disease and we were taught in medicine to assume the zebra uh too i'm sorry to assume the horse not the zebra which means

19:28 common things are common and you shouldn't be looking for unusual things all the time here is what i mentioned about carpal tunnel earlier as a red flag and here's what i mentioned earlier about orthopedic finding that about a third of patients who have lumbar stenosis the tissue stains positive for amyloid so if you have this surgery done on one of your patients call the pathology lab and ask them to stay they usually keep these slides around for quite a while and i often go back and ask the pathologist even if it's done in an outside institution to stain the tissue if i'm looking for the diagnosis they're trying to confirm let's focus now on the cardiac testing and and the two traditional things are the echocardiogram and the atrial

20:15 fibrilla and and the electrocardiogram electrocardiogram on the left uh your doctor will notice that the voltage over here or the amplitude of the spikes in this side tends to be very very small and the amplitude of the spikes on these three leads tend to be small on the other hand the heart is very very thick as you can see here on the echocardiogram so the combination of an echo that shows a thickened heart or a lot of mass and an ekg that shows low voltage or low mass is very helpful it's suggestive but it's not diagnostic of ambulance there is a new tool with echo that we've used and it's something called strain and it's easy to do

21:01 when the heart shortens uh contracts like any other muscle it shortens and we can measure the amount of shortening it does and we can put this on a polar clock and we can measure the amount of negative or shortening that there is now the number should be minus 20 or more often what happens is amyloid is we preserve this strain or shortening at the apex or the middle of the heart where the rest of the heart has lower numbers called 10 minus 9 minus 8. we call this pattern as a cherry on top because it looks like a hot fudge sundae with a cherry on top and again it's very very suggestive and if you find the santoneko it's probably an indication to look further for amyloid in the patient regardless of whatever symptoms they

21:46 have i'm not going to go into cardiac mr but there are a variety of ways that cardiac mr is helpful and consistent with the diagnosis it's not enough to make an absolute diagnosis but there may be dead on cardiac mr that may help in the future allow us to follow disease without giving more radiation to patients but what's been the game changer is a test called the pyp imaging or a pyrophosphate scan for cardiac amyloidosis it's a relatively simple scan to do we inject a very safe tracer called technetrium pyrophosphate that's been around for 30 years when you looked in that picture of me from way back when we were injecting it to people in the cardiac care unit to see whether they had myocardial

22:32 infarction because it bound to calcium as you can see in this picture where the heart is very very well delineated in patients who have tt or amyloid there's a significant uptake of tracer whereas in no other diseases really besides amyloid you have up and there are several different ways for your doctor to be able to measure this one is by what's called the semi-quantitative scale or the perigeni scale that they may talk about but we grade between zero and three zero is no uptake in the heart one is less than the rib but there is mild uptake two is equal to the rib and three is uptake that's greater than the root and

23:18 if you have grade two or grade three it is diagnosis of amyloidosis most likely ttr amyloidosis if you have grade zero and in most patients with grade one it's not consistent with tdr amyloidosis we can also do it quantitatively by actually drawing a circle around the heart and a circle around the other side of the chest and compare the uptake uh between one side and the other and we can make a measurement and if the ratios are either greater than 1.3 or greater than 1.5 depending on the time of imaging they're consistent with amyloid now most of the time high levels of uptake are consistent with wild-type

24:04 uh ttr hereditary amyloid but occasionally you can see you can have mild uptake uh consistent with al amyloid so although this is the diagnostic test for ttr amyloid you need to rule out ammo al amyloid also we do spect imaging and we do pet imaging and i think dr wahl is going to talk a little bit more about that later but to inspect imaging allows us to tell whether the uptake is definitely in the heart or just in the blood pool you can see here we've outlined the heart with tracer we've outlined the heart with treasure and has made it much clearer and much more definite for us to make a diagnosis of positive versus negative but as i said you need to rule out al amyloid because patients with al amyloid may have mild

24:50 uptake so everybody needs to have the traditional testing for al amyloid serum amino electrophoresis urine immuno electrophoresis serum free light chain assay and kappa lambda ratio over on the right you see in anaphyla and amyloid center it's done about a hundred percent of the time in settings that are not an amyloid center it's only done about two-thirds of the time so you need to make sure if you or your family is sent for a pyp scan before they make a final diagnosis they've ruled out al amyloid also so if we want to sum this up what is the diagnostic process for somebody who we're considering by the big picture of amyloidosis ttr we start out with the ekg and the echo

25:36 we make sure we've ruled out al amyloid we do a pyrophosphate scan if the pyrophosphate scan is positive by inspect and by planar imaging we then go on to make the diagnosis of ttr amyloid but then we have to know whether it's the wild type or the genetic form so we then go on to uh genetic testing and we can decide then whether it's ttr hereditary or ttr wild type let's move on now to treatment either the treatments that are available or will be available in the future we'll talk about it over time but there are stabilizers there are uh

26:22 vibrant destabilizers there are silencers of the rna that makes the protein and then we're looking into uh antibodies monoclonal antibodies against the uh amyloid fibrils themselves but before we go on to disease modifying therapy i want to talk about medical therapy for amyloid and i think this is one of the reasons that you need to go to a cardiac amyloid center if you have amyloid with heart failure because a lot can be done just by modifying standard therapy the traditional diuretic we use is furosemide in amyloid i tend to use torsamide or bumetadine because they have better abdominal absorption and people who have swollen bellies do not absorb drugs well

27:09 i teach people how to take their own diuretics after uh two or three times when they start to gain three to five pounds they can learn to take a drug called metallozone on their own and help them get back down to their baseline that way they don't have to come into the hospital every time they start to gain weight and get shorter breath aldactin is a drug that we use for heart failure and may also be useful in preventing atrial fibrillation and preventing remodeling it's safe and effective we adjust the diuretics based on clinical status not the bu and the creatinine so we follow labs to make sure we're not in a danger zone but really finding the appropriate level of volume in the patients what's important traditionally we use drugs called ace inhibitors or angiotensin receptor blockers or ironies

27:58 uh a drug called intresto that you see ads on tv these are standards of care for people who have systolic heart failure that as you'll see they don't work that well in patients with amyloid we avoid beta blockers because patients need a high heart rate we avoid calcium blockers and hydroxide because uh these drugs bind into the uh amyloid fibrils and then the patients become toxic and many people have orthostatic hypotension and so we can give them a drug called midadream to help them maintain blood pressure patients with amyloid are really very very sensitive and you have to be very very careful to make sure they're not too dried out traditionally in heart failure when a

28:43 patient presents to me with swollen legs swollen belly and short of breath and i give them diuretics and they come back to me and the next week the nurse said well they lost four pounds and i walk in and they say how do you feel and i say miserable and it took a while to learn that that's a common finding with amyloid because what happens is you give them diuretics but you decrease the blood volume and you decrease the filling of the heart so look at this bucket brigade and think of the bucket brigade of your heart pumping and each one of these buckets is a contraction of the heart well supposing you have a small stiff heart like you do in heart failure or preserved ejection fraction well even though the heart's pumping appropriately

29:28 because the heart's not full you're not going to get enough water over to put out the fire supposing however you have somebody who's not strong enough because they got their weak to really keep the bucket brigade going that's what systolic heart failure is so the heart may be full but not pumping enough blood and if the organs don't get enough blood that they don't work well i mentioned that we don't use the traditional heart failure medicines and this is a look at both what's called the ace inhibitors and angiotensin receptor blockers and the beta blockers and following these people over time and you can see that these people do poorly compared to the patients who don't get these drugs so you need to be cautious in this unless people really have severe weak and heart

30:14 muscles atrial fibrillation as i said is common in these people way before they have heart failure often a patient will come to me with a history of atrial fibrillation and they've been cardioverted four times or they've been on three medications or they've had an ablation two or three times or they need to have a pacemaker put in and this difficult to control atrial fibrillation is a very common presentation of amyloid ttr these people need to be on blood thinners or anticoagulants because they have a high thrombotic wrist they're highly likely to embolize and throw and have strokes we need again to be cautious with drugs that control the heart rate usually we try and keep people in atrial fibrillation with heart rates around 60

31:00 to 80. because i've just talked about before often i let their heart rates rise between 80 and 100 for those people with advanced disease we're beginning to see cases of liver transplants or combined liver heart transplants in patients who have particularly the v30 uh mutation um in our institution we've started to do on-block transplants of heart and liver so it's one procedure for both take the whole thing out and put it back in a single patients and the experience with this although small had been very very favorable so let's go over traditional therapy now let's go over disease modifying therapy and i say that the era of therapeutic nihilism is over which means we can no

31:46 longer say we have nothing to do to address this disease or modify this disease and i said we can block the protein development we can stabilize the tetramer prevent it from breaking down or eventually maybe we can find a way to eliminate break down and remove the fibers so let's talk about some of the drugs that are available we have two drugs that are called silencers one is called patisserin which is an rna interfering agent one is called the initersion which is an anti-sense all of the nucleotide and both of these prevent the formation of the abnormal trans-thyroid patient is a small molecule it's a proof of hereditary polyneuropathy which means

32:31 it's not approved for wild-type amyloid and it's not approved if you only have hereditary cardiomyopathy it's given every three weeks by an infusion in an infusion center patients are pre-treated to reduce the infusion reactions but after the infusion there are very few side effects this is some of the neurologic data and it just talks about neurologic function and without going into details you can see the patients that receive patient and the dark blue did much better than the patients who received placebo there was also a pre-specified group of patients who had cardiac involvement and in that particular group we actually saw some markers like i talked about bnp

33:17 we talked about strain we talked about some early echo findings and these were actually seen in this particular group up to three years some early suggestive findings that this drug may also work for cardiac involvement and there are studies now going on to look at this the other silencers are draw called linotersin it's an antisense drug that decreases the productions of trans cyrene it too is approved for only h8tr polyneuropathy it's given at home by sub-q injections the side effects include low blood platelet count and a hemorrhagic kidney dysfunction but there is a uh what's called a rem monitoring program which allows the patients to have blood drawn weekly

34:03 that's decreased the likelihood of major side effects and i have not had any major side effects with this monitoring program in addition to the neurologic improvement however we see that the patients have reduction of left ventricular mass and we've improved what's called a six minute walk here's an example of that data by by merrill benson small numbers of patients but you can see uh strain got better six minute walk got better left ventricular thickness and left ventricular mass which are a reflection of diastolic dysfunction all got better the major drug though that was approved last year was a drug called the feminist which was uh approved in a major based

34:49 on a major study called the attract study written by matt maurer last year in uh new england journal of medicine and what it does is stabilizes this tetramer to prevent it breaking down into the monomers and the formation of fibrils it does not take away the disease it does not take away the fibrils but if you compare survival in patients who receive to feminists in the blue the patients who received the placebo you can see there was an improvement in survival and the number needed to treat was only seven patients before you saw improvement in survival the downside of this curve don't separate until around 15 to 18 months we're still learning why it takes so

35:35 long for the curves to separate we're still learning a little bit more about when patients actually may feel better i have patients who not only stay stable but actually do feel better around six months and that goes along with the quality of life study a six minute walk is really a simple test you tell patients to walk six minutes and you measure how many feet or how many meters they can walk you let them walk on their own they shouldn't be prompted they shouldn't be prodded they shouldn't be spoken to you should just stand behind them watch them walk six minutes of what's their regular pace not fast and see how far they do and it's been a good marker for uh following cardiac function it's a good marker for following uh patients who may go on the transplant

36:21 and i believe also that it's a good marker for following people who have combined neurologic and cardiac involvement with ttr and you can see here at six months the curve started diverging in terms of six minute walk in patients who received the fabulous versus the patients who received placebo other medicines we can use uh as i said uh to families is a uh stabilizer there's another drug out that can be used off label called diflunasol it's a non-steroidal arthritis medicine there are small studies that show it may be helpful with similar effects to defamitous there are some side effects in terms of worsening renal function abdominal pain gi bleeding so its use in

37:07 an elderly population is somewhat limited green tea extracts have been shown to decrease lv mass and i give that to patients routinely doxycycline and antibiotic has been shown to promote fibro degradation particularly when used with the bile acid tudca small studies show that it may be effective the problem with long-term use of doctory cyclin is it makes your sons for who has a uh lives in florida that these people become sensitive to sun and it doesn't work well so this is some of the ongoing research

37:53 as you can see here there's the apollo b which is looking at patisserie the helios b looking at vitreous iran which is a derivative of patisserin being given every three months there is the iona study that is looking at a sub-q injection of a drug similar to um inotierson interestingly you can use sephaminus in this so we may see the benefits of dual therapy ag-10 which i have not talked about is another drug that's in study that actually has a very favorable effect as a stabilizer in terms of improving six minute walk and prx is the antibody which is an early study so there's a lot of hope for

38:40 ongoing research into this field people asked last week about coronavirus uh and uh the relationship between amyloid and coronavirus we just started an international registry that we're going to be following this we don't have any answers on this but obviously these people people with ttr amyloid do have heart disease should be considered at high risk and should be very very careful now that our country is opening up and making sure they are following the strictest of rules and not enter societally openly for quite a long period of time we have an amyloid center at cleveland clinic joint jointly run by florida and cleveland and

39:27 we have a cleveland clinic uh facebook site that provides ability to interact uh this will give you supplementary information we work with the amyloid support group and it's a way to find out a little bit more and communicate with other people and with that i'll stop and there'll be time for questions later and i'll look at the handwritten questions uh that are in the q a right now and i'll turn things over to muriel thank