So Jill and Gabriel, I can start off. We have some questions on the side. And then it is my understanding you guys may have some questions for each other, which will also be very, very good for us all to hear.

So one question that I saw on the side, and I think this is a good multidisciplinary-type question. So the question reads, any suggestions on how to document in a hospital setting when you recognize what would have been early red flags? For example, all the classical signs and symptoms suggested in bilateral carpal tunnel release 10 years ago, and previously seen by a cardiologist, but do not want to offend. How would you handle this situation?

Jill Waldron: I do not think that a cardiologist will get offended. But one thing that I try to do is we have our own problem list all the time, and I will add it. And so if I have done a workup, I will put what I put the workup on, even if it is negative.

And I may sometimes also in my assessment and plan, I will put, "Consider this for the future," or "We thought about this," but making notes so that the person who sees it the next time can pick up where you left off. And oftentimes, it works. Oftentimes, then the next APP after me will see it, and they will order it, even though the cardiologist that I was with said, "No, we do not need to look at that," because I did not mention it to the patient. And so you are not offending. Maybe you are attending.

But the new cardiologists or whoever see it in the future may not. They might have a different perspective. I do not know. We have a group practice, though. It might be different in your setting if you work with the same attending over and over again. Then I would just try to bring it up over time and really have some confidence in being able to state why you think it.

I think one of the very first times that I built up a little bit of respect for one of my colleagues from one of the cardiologists I work with was when he was seeing his very own friend as a patient over and over again every year. And I would see it with the same doctor instead of with the whole group practice. And one day, I told him, "I want to work him up for cardiac amyloidosis."

And he was like, "No, why? Why would you want to do that? He has this and this and that. It could be explained by so many other things. Let us not put him through that."

And I was like, "Yes, but, you know, he also has this and this, and these are newer signs that I have just actually been learning about. And it is really not that expensive to do a PYP scan. And I think that his insurance will pay for it. And sometimes, you know, you will have some that come back that are negatives. But if you do not ever look for it, you are not ever going to find it."

So he is like, "Fine." And he gave up with me because I was being a little bit more confident in doing that.

And then it turned out he had amyloid, and he was shocked. He is a brilliant physician. But he was so shocked that he brought it up to all the other cardiologists in one of their meetings and said, "Look, our APPs can look for this, and they are finding it, and you need to listen to them when they come up with it. They want to look for this."

And that was very satisfying. But at the same time, it was a great learning experience too, that sometimes you just have to, if you really feel strongly about it, you can push for it.

And I think a lot of times, some of the doctors are really busy with procedures and research studies and all the things that they have to do that they look for the standard thing that is most common. And this is sometimes a little bit of a zebra. And so sometimes it takes the person that has a little bit more time to step back and see the bigger picture.

So I do not know. What do you think, Gabriel?

Gabriel Dascanio: Yes, no, I think, you know, amyloid, especially that a lot of the symptoms are so vague and they can be explained away by other causes. And it is very easy just to say, oh, it is due to this and that and something else. It is not amyloid.

And if you do not have amyloid on your mind and you are thinking about that in your differential, it is very easy to miss. You know, you could also think about just calling up that attending, and having a discussion, "Hey, have you thought of this before? You know, do you think that would be something that we should work up?"

You know, in our facility, our general cardiology team does not have a lot of time for all their visits. And so it can be very hard to find some of these more nuanced diseases. And so that is where also talking with your other departments and letting them know that, hey, you are looking out for amyloid. If you have an amyloid-specific team, that is a way that we get a lot of our referrals. You know, they may just have a suspicion for it, and they will send the patient to us so we can work them up properly.

You know, if you have a suspicion, find your nearest amyloid center and place a referral. That way they can be worked up for it because, yes, you do not know until you know. And you have to be able to rule it out to say for sure that they do not have amyloid.

Jill Waldron: Yes, that is a good point about the referrals. And I think sometimes I tell patients, you know, I am going to refer you. I mean, for me, I am referring them anyway because I am going to end up seeing them.

But if I am seeing them in my heart failure clinic, I am going to refer you to this amyloid clinic. And I tell them, "Do not go look it up online. You are going to get a lot of misinformation if you do. But you are going to meet with some people that are really going to get to some of the bottom of these things. And it may not be anything. You might not have this at all. But I think that it is worth looking into because there is treatment, and your quality of life will be much better if we find out and you do have it."

And so I think, you know, if you do not feel comfortable or your team is not willing to work it up, you could also definitely refer to a center of excellence or somewhere where they will work it up, too.

Dr. Giaconoa: Thank you very much for sharing that case, Jill. That is amazing that you convinced him to get the workup. And that segues, there is more of a comment, not necessarily a question, but I think it is probably true that somebody wrote that this diagnosis must bring an inadvertent relief to the patient since they find the answers to the many lingering multi-system symptoms they have chased their entire life.

So instead of explaining all these things away, we can now tell them that it is all linked, and we can help them feel at ease, I guess, about it. Do you guys feel that that is how you have some relief from your patients when you guys diagnose them?

Gabriel Dascanio: It is a combination of relief and surprise that I get. You know, some patients are very relieved, and they are relieved that there is something that can slow the progression because they have noticed over the last couple of years, they just cannot do what they used to. And I will tell you, most of them will say, "I thought I was just getting old, you know, and I thought this is just what I should expect from the rest of my life."

And starting them on treatment, amyloid-specific treatment, managing their heart failure better, a lot of them are able to get back to a better quality of life than what they were currently at when we first started seeing them.

Jill Waldron: And people are actually sad when their test comes back negative. Not usually. Usually they are relieved. But I have actually had some that are sad because patients do want to know. And I think that also goes back to the old days of the myths of, well, should we even work this up because they are in their 80s and they are doing just fine. But there is treatment.

And even if there was not treatment, I often tell them, "Let somebody else worry about the treatment." But just having an answer for what this is and being able to sometimes really just helps to just go, "Oh, okay." Labels are appropriate if they are their correct label.

Dr. Giaconoa: That is a good point. When I do secondary workup for hypertension, if I get all negative, sometimes my patients are also the same, "Well, then what is causing my high blood pressure? You could not find anything?" So I do understand that as well.

So moving to another question. So one of the audience members wrote in, do you find that patients with amyloid have symptom progression that is more sudden, develops over 1 versus 5 years, or it is even slower?

Jill Waldron: That depends. Hereditary patients that have Val142I can really progress quickly, and they can present in shock and be in the hospital. But for the most part, ATTR is a slow, progressive disease, and it takes years. And even if it takes them a couple of months or so to get on therapy, it is not the end of the world because it is a slow progression.

But the studies all show that around 18 months, there is a difference in mortality. Some have some improvements with quality of life as early as 6 months. Some of them are still more around 1 year and 18 months. But patients, I tell them they are not getting better. The curve is still going down, but instead of going down like this, it is going down like this.

And they do tend to feel better over time if they miss their medications. For some reason, they cannot get it filled at the pharmacy or whatever. And they will go without, or they are in the hospital, and they will not give it to them while they are there for like 2 weeks or so.

Then they will say, "Oh, I really feel a difference." But when you start them on the medications, they do not feel a difference. They are like, "Mmm." Because it is such a slow decline. And if you do not have treatment, it is a pretty more rapid decline.

When I saw patients in the early days before we had FDA-approved medications, I had patients that would come in rarely for hospital admissions, sometimes on a gurney because they could not stand up because they were so orthostatic. So without treatment, they will decline quicker. But on treatment, it is really, really slow progression.

Gabriel Dascanio: Yes, I have found that too. Although we did have one case earlier this year where from diagnosis, his echo, he had FF, still preserved EF. Within 3 months, his EF had dropped to about 25%, and he ended up getting a heart transplant about 6 months later.

So he progressed very, very quickly. And then yes, others where we have been monitoring them for 7 years and they continue to do fantastically, and their quality of life is fantastic.

Jill Waldron: Yes, definitely varies.

Dr. Giaconoa: Pretty heterogeneous population, it sounds like.

Okay. Another question. Is there a specific beta blocker better for ATTR with people who have arrhythmias? And then the same question with diuretics. Furosemide, Bumex, Furosemide, etc.

Gabriel Dascanio: I have found that I have had more orthostasis if patients have been on carvedilol versus like metoprolol succinate as well as you can do, you know, it is once-a-day dosing and you can dose the metoprolol like at bedtime. So they tend to have less daytime side effects from that. But in general, they just do not like beta-blockers. They do not tolerate them well.

For the diuretics, that is very patient-dependent, I feel. I tend to change up my diuretics pretty quickly. Patients will get tolerant to them very quickly, and they just respond differently to different diuretics. Bumex and Furosemide, they have more bioavailability. So those do tend to work a little bit better sometimes, but everyone can be slightly different.

And I would just say if you are going up on your dose of diuretic and it is not having the intended effect, go ahead and try switching to a different one and see if you get a better effect.

Jill Waldron: Yes, those are great. I definitely would stay away from carvedilol. metoprolol is better for so many reasons. Sometimes bisoprolol if they cannot tolerate metoprolol, but usually if they cannot tolerate metoprolol, I do not even put them on a beta-blocker. I just stop it. And if they need something for rate control, then usually even just 12.5, if they are HFpEF.

There is some newer guidance in the 2025 European Society, the ESC guidelines this year in July, that shows that you can use beta-blockers for someone who has a low EF, but they recommend you just do just a tiny bit and you do not up-titrate them like you do with our normal HFpEF patients. There is maybe a slight mortality benefit, but for the most part, these patients, a lot of them, were just peeling stuff off just to keep their blood pressure up. And that goes for the diuretics too. The diuretics are always a tricky balance because patients who have amyloid, their heart failure treatment is so different than other HFpEF patients.

And because they are so restrictive, their blood pressure can change a lot just by going up on their diuretics, whereas that does not usually happen with other HFpEF patients. And so a lot of providers will leave them wet, and they will just be like, "We cannot go up on your water pills because you are not tolerating them and your blood pressure drops and you are orthostatic, and we do not want you to fall, you are already falling." But I have actually found that a lot of these patients who are orthostatic, you can push the diuretics if you can give them just a little bit of Midodrine. And sometimes a lot of Midodrine, sometimes other combo meds to keep their blood pressure up, but they will feel better and they will live longer if their NT-proBNP is less than 3,000. And so we monitor those frequently.

That is not always the goal. Sometimes they are chronically at 5,000. But if you can get that NT-proBNP down, then their prognosis will improve. And they are not as likely to be hospitalized. So I do use a lot of Torsemide and Bumex. Lasix for the very early stages. And if they are not on anything yet, I try to start them, like you had mentioned, the SGLT2 inhibitors.

That is one of the few medications of the GDMT that we do have a lot of evidence for, for amyloid, that it is helpful. It is especially helpful the more restrictive they are. So sometimes you can avoid even starting a water pill in the first place by starting that one first.

So that is the most important one if they do not have any major red flags that they should not be on one. But yes, those, I would say, metoprolol, Torsemide, Bumex, and even before them, SGLT2 inhibitors.

Dr. Giaconoa: Yes, I love the discussion of blood pressure management in these patients, because like I said, some of them I found, they were actually presenting with really bad autonomic dysfunction. So I guess one, and it does not surprise me at all that they are so sensitive to beta-blockers. In general, with autonomic dysfunction patients, it is good to avoid beta-blockers.

But in the case of amyloid, as you guys had already mentioned, that deposition in the peripheral nerves impairs their reflex, their baroreceptor reflex because of efferent sympathetic failure. And so they are already having trouble releasing norepinephrine when this person stands up, or beta blockade on top of that, they are even more sensitive to it, which makes complete sense why you guys see such sensitivity in patients with amyloid in terms of carvedilol, for example, dropping their blood pressure, making their neurogenic OH worse. And definitely Midodrine can be useful in those patients.

I was not so sure about it, about using Midodrine in those with ATTR cardiomyopathy. So this is educational for me too, because I mean, I will use Midodrine and neurogenic OH without ATTR, but it is good to know that you guys are okay, that you feel like it is okay and safe to use Midodrine in those too.

Jill Waldron: And I think 5 mg TAD is the usual starting dose. But if you are not sure, you can even start at 2.5 and then go up. These patients are not going to get super hypertensive – rarely. If they are getting hypertensive, then they are not truly orthostatic yet. But if you have demonstrated that they are orthostatic, and I tell patients too, "I am glad you are telling me what your sitting blood pressure is, but I do not really want to know what your sitting blood pressure is all the time. It is okay. It is good because it gives me a general idea. But when you come into clinic, I want to know your supine, you are standing at 1 minute, and you are standing at 3 minutes. Because if you are dropping while you are standing, that means you are not going to be functional. You are not going to be able to do all the things you need to do at your house. And I want to know what is your supine so that I am not going to make you go too high when you are taking Midodrine at bedtime."

So the sitting blood pressure, they are like, "Oh, I am always fine. I am always fine." But if you can demonstrate orthostatic hypertension, true orthostatic hypertension, Midodrine is like the biggest save. And then there are others too, but you have to learn about them.

And our neurologist has taught us about them. So I feel super comfortable in adding other things like droxidopa or pyridostigmine. But I would recommend that if you are not used to that, that you get a little bit more education before that.

But bringing down their fluid is super important, but you have to balance it out with their blood pressure.

Dr. Giaconoa: Everything you said was music to my ears in terms of sitting blood pressure, titrating medications, sustaining blood pressure, being careful for supine hypertension when using Midodrine, especially in the late afternoon. I typically tell them to avoid going to sleep if they have taken it for a few hours. Yes, everything you said was, again, music to my ears.

I agree with everything. Generally, we try to go with pyridostigmine just because we are very timid when it comes to supine hypertension in patients with really bad neurogenic OH, but I agree. All the above was fantastic.

So I do not want to hijack the conversation.

Jill Waldron: No, you are good. I just want to add, though, that with pyridostigmine, for a lot of these patients, they are already super constipated. And so one of the side effects is that it will loosen their bowels. Sometimes it will make them have diarrhea.

So if that is the case, then pyridostigmine is not always the greatest. But that is one of the things that the neurologist had taught me that really helped because you are helping 2 things at once when they are so constipated, and then you are keeping their blood pressure up.

Dr. Giaconoa: I completely agree. So let us see. We have some other questions.

So there, for anonymity, I will change this one a little bit. But there is a patient who is 83, has a lot of red flag symptoms, and no one has suggested ATTR. He has HFpEF, bilateral leg edema, bilateral carpal tunnel, non-diabetic foot neuropathy with a clean recent heart cath, normal pressures, no valve disease, and hypertension that has improved.

Should this person be pursued with light-chain testing and scintigraphy for a diagnosis? His main symptom is dyspnea on exertion.

Jill Waldron: I think I would want to have some more objective evidence first. You have 3 out of the 5 red flags. You have heart failure. You have the peripheral neuropathy and the carpal tunnel. But I would want to know if there was anything else by EKG, by echo, something else like that.

And I would throw in a plug there that if you have a great orthopedic team, that if they have not had carpal tunnel surgery yet, sometimes these hand surgeons, if they are getting carpal tunnel surgery, they will take a sample then before it ever develops in their heart.

But before it is in their heart, I have made the mistake of working up too many people that did come back negative because they did not have the objective evidence also. Because they probably did have it, and some of them maybe would, will, still yet, but we are looking a little too early. And we want you to look early, but you also have to recognize that if it is in the heart, there has got to be something that is showing up somewhere.

Gabriel Dascanio: Yes, I like that you brought up the orthopedic team. Our orthopedic surgeons will actually send out biopsies for carpal tunnel for Congo red stain. And, you know, we get a lot of patients for that and they have no other symptoms, and their echo is completely clean.

We will go ahead and get the blood work on them. But a lot of times it is just monitoring their echo to see if they have any disease progression. But they really do not have any cardio manifestations or any neuropathy other than the carpal tunnel that has been taken care of.

Jill Waldron: In my world, I call that orthopedic ATTR. I do not know that that is in the literature yet, but that is how I frame it because they do not have any cardiac evidence, right? But you have a positive carpal tunnel, or I have had a positive spinal stenosis. And I am just curious what you do then, because that is a tricky conversation once they refer you to you. Some of our patients that are like that, we have put them on Diflunisal and some of them, their insurance has also covered a stabilizer. I am just curious if you just let it go and just monitor them or how you would handle that.

Gabriel Dascanio: Yes. I mean, the majority of the time we are not able to get them on anything. Insurance will not go for it. They do not have any other proof of amyloidosis. If the patient is very concerned and persistent about it, we can do further testing, like a PYP scan. Generally, would recommend against a biopsy at that point. I think Duke, so Duke is close to me, and they are doing some research on that early-stage amyloid.

If they have carpal tunnel, but no cardiac involvement, looking at if, you know, starting them on tafamidis is going to make a big difference in their outcomes later on. You can still get genetic testing as well. I think that is important, especially for family screening.

We have had maybe 1 or 2, and with neurology, and they had some other peripheral neuropathy that they were able to get on a Eplontersen to treat that. But in general, we are monitoring these patients.

Jill Waldron: Yes. I like that point about the neuropathies at that point too. That is good. Yes. Sorry, just wanted a little side note because I think that we are going to see more of that in the future.

Gabriel Dascanio: Yes. Yes. And it is tough because the patient has this concern they have read up about it, and it is like, well, what do we do now? And so that it is a lot of education and reassurance for the patient.

Dr. Giaconoa: We have one last question from the group. I will go ahead and ask. So I believe this medication is used for Alzheimer's, lecanemab.

So the question is if lecanemab is used to target amyloid beta plaques in Alzheimer's, what is the likelihood that it may work for cardiac and peripheral deposits of amyloid? So I have an idea personally, but I also want to hear what you guys think about that question. Are you guys familiar with that medication?

Jill Waldron: I have heard of it. Sorry. Can you, can you say the whole question again, though?

Dr. Giaconoa: So the question is if lecanemab is used to target amyloid beta plaques in Alzheimer's disease, what is the likelihood that it may work for cardiac and peripheral deposits of amyloid?

Jill Waldron: Okay. So this medication, I believe, is a monoclonal antibody. Is that right?

Dr. Giaconoa: I believe it is. It typically targets amyloid beta.

Jill Waldron: Yes. So the beta amyloid is different than the TTR. So we mentioned there are over 42 different types.

We get this question a lot too. When you ask about which questions, a lot of them are say, "Is this going to affect my memory?" And we often will say you could have some memory loss from other amyloids, but this particular one has never been associated with that.

And so that is also helpful for patients to understand that each beta or each amyloid, whether it is beta or TTR or whatever, has different treatments. And you cannot assume that just treating one is going to treat them all. There are coming out with some pan-amyloid imaging that you will be able to one day see all the different amyloid deposits in your body. But there are also some other research studies out there on monoclonal antibodies for cardiac ATTR.

And they are ongoing right now. They are fully enrolled. We should probably have data within 5 years unless they stop sooner. Maybe even 3 years that will break up those amyloid proteins that are already there, but they are not currently FDA-approved. And yes, we do not have crossover from other amyloid treatments to TTR.

Dr. Giaconoa: Excellent. Okay. I think we can go ahead, unless you guys have any last minute questions for each other or key points you want to leave the audience with.

I will go ahead and start wrapping up.

Jill Waldron: Well, I actually do have a couple of questions for you, Gabriel, if that is okay. And I do not want to take everybody's time too much, but I think since we have a few minutes, it is fun to also mention research and things that are going on out there.

I wonder if you have noticed any difference in your patient population that has pacemakers, if there is a difference in biventricular pacing in amyloid patients versus like a single or dual chamber pacemaker.

And I just wanted to point out there also to the audience that in these newer 2025 ESC guidelines, you can have and recommend patients for CRTs, even if they do not have an EF less than 35% now. So if an amyloid patient has evidence of desynchrony and maybe their EF is 45%, but they have a high degree of RV pacing, then they are still a candidate for CRT.

And so the question is, does it make a difference long-term? And I do not know that we have that answer yet, but I wonder what you are seeing clinically, if any of your EP docs are struggling to put CRTs in or still, because I often have a lot of patients that I think should probably have CRT and the EP docs think, "Oh, we will just put in a single chamber, they are 90. We are not talking about defibrillators; we are talking about pacers." but I am like, why did you put it in a single chamber? So curious what your thoughts are.

Gabriel Dascanio: Yes. I mean, I really have not had too much of an issue. We work pretty closely with a couple of our EP physicians. And so we brought up that biventricular pacing and they are pretty acceptable to that. So we really do not have too much of an issue with them putting in a bivy pacer versus just a single chamber.

Jill Waldron: With a CF of 45%?

Gabriel Dascanio: That is a little difficult sometimes. And I think it is helpful. Some of these patients, they have intermittent bundle branch block. And so they are able to actually see something that is there for them to treat. And so they are a little more likely to do that. And then talking with them more about how amyloid progresses and causes so much of this conduction abnormalities, they are more willing to try to push for that.

If we can get the insurance to get on board with it, that is a holdup sometimes too.

Jill Waldron: Yes. I think that is going to be something that is new coming down the road. And of course, I have to always ask the unspoken question, that what is your center's thoughts on dual therapy with stabilizers and silencers?

Gabriel Dascanio: So that is a tough one. We do not generally do dual therapy on patients. We have tried starting patients on vutrisiran who are already on tafamidis, who are progressing very quickly. They are not a transplant candidate. There are no other advanced therapies we can do to help them. And so, we have had some where we have tried adding on vutrisiran to their tafamidis that they are already on just to see if we can slow things down even more.

And I do not think we have been successful in fixing their symptoms. But it does seem like things have slowed down just a tidge maybe in a couple of those. But again, there is no really strong data supporting dual therapy.

Do you guys do ever do dual therapy at your center?

Jill Waldron: We do. We have a few now, actually. We probably have about 15.

And we had to have a lot of great discussions between all of our cardiologists and come to a consensus of how we would approach it. So we would all do the same thing and not different things within our program. And I think every program is doing things a little bit differently because we do not have great evidence yet, right?

So the reason why it was not statistically significant in the HELIOS-B trial was because it was not ever powered to look for it in the first place. So it is not that it cannot be done. And some of our cardiologists, when they look at the curves, tend to think that it is a real phenomenon.

And we will probably learn more when some of these other studies like CARDIO-TTRansform are done. But the question is, economically, is it ethical to be able to just get maybe, if we are guessing, 5% more improvement in mortality for so much money? So I think that is why a lot of centers decide that they do not want to do dual therapy. And then it is a lot driven by insurance, of course.

But our center has decided, like you, for the very severe and sick patients. That is what we are doing. When they have a wall thickness above 2, they are being hospitalized. They have significant polyneuropathies that are affecting their function. Maybe adding acoramidis around to it will help so that their polyneuropathies do not progress so much and they can stay physically mobile a little longer.

So I just was curious. It is a fun question to talk from center to center because we do not have any guidelines out there. And each center is doing their own different thing right now.

Gabriel Dascanio: Yes. And I think that is also why we have pushed for early recognition. We have had lots of outreach to other cardiology groups in our area within our general cardiology group here at Atrium to raise the awareness to get that diagnosis earlier and sooner so that if they do progress quickly, then they might be still young enough and good enough to get a heart transplant. We might be able to do advanced therapies rather than shoot in the dark and hope that dual therapy is going to get them a little bit more.