Dr. Giaconoa: And so with that being said, I will go ahead and hand off fundamentals 2, which is personalizing ATTR cardiomyopathy treatment with novel stabilizing and silencing therapies, to Gabriel.

[00:48:22]

Gabriel Dascanio: All right, so treating both ATTR cardiomyopathy and heart failure symptoms. Symptomatic heart failure treatment in patients with ATTR cardiomyopathy is not quite the same as treating regular heart failure. You have to be really cautious with the beta blockers, ACE inhibitors, ARBs and ARNIs. Again, a lot of them are going to have those AV blocks. They are going to have orthostatic hypotension, and they are just not going to tolerate those treatment options.

Diuretics are really needed and oftentimes at a higher dose. These patients really will build up a lot of fluid with those restrictive ventricles. You have to still monitor them pretty closely, watch for renal dysfunction. Definitely can consider a loop diuretic plus an MRA. I would also like to add SGLT2s into that one. We find that those really do help with the symptoms that a lot of these amyloid patients have.

Digoxin can be used to rate-control cautiously with close monitoring. Rhythm management is difficult with these patients, and I would really like to say that getting a multidisciplinary approach for these patients, involving electrophysiology early on, is really important. Atrial arrhythmias are hard to treat with them because those ventricles are stiff, their atria will dilate out, they will develop a lot of AFib, and it is really hard to get that rhythm management for them. If you can consider catheter ablation and consider it early on, you can also use amiodarone.

If they do develop AFib, anticoagulation is really important for this patient population. They should really be anticoagulated regardless of their CHADS-VASc score. They are at a much higher risk for developing those clots and having strokes.

Then again, be on the lookout for if this patient needs a pacemaker. If they are having all these arrhythmias and you are limited by their heart rate, they are having high-degree AV block, adding in a pacemaker, now you can use some of those, and you are not having to worry about them becoming so bradycardic.

[00:50:38]

Getting into amyloid-specific therapies, some definitions, siRNA: double-stranded RNA that binds to RNA-induced silencing complex, causing targeted mRNA cleavage. When created in a lab, these are called synthetic interference RNA.

Antisense oligonucleotides, these are single-stranded RNA that binds directly to the targeted TTR and RNA. Basically these are inhibiting production of TTR and slowing disease progression.

[00:51:10]

Then we have our stabilizers like tafamidis. It is a daily oral agent that is a derivative of benzoxazole. It binds to thyroxine-binding sites and prevents dissociation of tetramers. You are stabilizing that TTR tetramer, and preventing it from dissociating into those monomers and depositing throughout the body.

In the Phase III ATTR-ACT trial, it showed a decrease of all-cause mortality, cardiovascular related hospitalizations, and it slowed the decline in functional capacity and quality of life versus placebo at 30 months.

The ATTR-ACT long-term extension study found tafamidis 80 mg provided significantly greater survival benefit versus the 20 mg dose with a follow-up of 51 months. Then another study found that tafamidis plus optimized background therapy improved exercise capacity in patients with wild-type ATTR cardiomyopathy. Again, going back to you cannot just treat the amyloid with amyloid-specific medications, you also have to treat the underlying heart failure and arrhythmias that these patients have.

[00:52:22]

Another stabilizer is a daily oral agent that binds to thyroxine-binding sites and prevents dissociation of tetramers. Phase III ATTRibute cardiomyopathy trial demonstrated significant benefit in 4-point primary endpoint (all-cause mortality, cardiovascular-related hospitalization, NT-proBNP levels, and 6-minute walk distance) versus placebo at 30 months, and these patients could use tafamidis after 12 months.

The ATTRibute open-label extension study found that continuous acoramidis therapy offered sustained benefit through 42 weeks versus those who switched from the placebo, and those patients could not use tafamidis.

Diflunisal had an off-label use. It is an oral NSAID that binds the thyroxine-binding sites and prevents dissociation of tetramers. That is one that we really do not use in our clinical practice at all, so I will not go into that one too much.

[00:53:22]

Vutrisiran, that one is delivered subcutaneously. It was just approved in March 2025 for adults with hereditary or wild-type ATTR cardiomyopathy. Phase III HELIOS-B trial evaluated vutrisiran 25 mg every 3 weeks versus placebo for 36 months. And an interesting note, greater than 50% of these patients also were receiving tafamidis during this study. So it is the first time that we had some data on dual therapy. What they found was a reduced risk of composite all-cause mortality and recurrent cardiovascular events by 28% versus the placebo.

Reduced risk of all-cause mortality of 35% at 42 months, but it was not statistically significant with combination therapy versus monotherapy. So in general we do not recommend using dual therapy using acoramidis and vutrisiran or tafamidis and vutrisiran.

There was a favorable benefit seen in functional capacity and health status at 30 months and a significant improvement in quality of life and 6-minute walk distance.

[00:54:36]

Eplontersen is a subcutaneous medication that is conjugated to N-acetyl galactosamine-containing ligand, improving its potency and selectivity for hepatocyte uptake. Phase III CARDIO-TTRansform trial is underway, but it is not yet approved for ATTR cardiomyopathy. It is used a lot for peripheral neuropathy.

We do have some patients that are on this medication. In general, we have referred our patients to a neurologist. They have to prove that the neuropathy is caused by amyloidosis, and then they are able to start this treatment.

Inotersen, again, that is one that we really do not use much clinically. It is delivered subcutaneously, and it inhibits liver production of TTR. There has been no trial dedicated to ATTR cardiomyopathy yet.

And then Patisiran is an older agent. It is delivered intravenously. The Phase III APOLLO trial showed significant improvement in neuropathy versus placebo in patients with hereditary ATTR peripheral neuropathy. The Phase 3 APOLLO-B trial demonstrated statistically significant benefit in function capacity and quality of life versus placebo in patients with ATTR cardiomyopathy, but the FDA denied its approval. So again, not one that we really use consistently in our clinical practice. I do have some patients from way back before tafamidis and acoramidis and Patisiran were options that were on this at one point, but they have since been switched.

[00:56:15]

So some considerations for current treatments. Comprehensive follow-up for monitoring the disease progression, some things you can do is monitor their 6-minute walk test; monitor their ECG. We will also do Holter monitors for 7-14 days. You can monitor their troponin levels. Another thing, if you have access to it, is getting a cardiopulmonary stress test and monitoring their VO2. And again, that is also helpful if you are considering more advanced therapies for these patients who might be progressing a little bit faster and those patients who would be a good candidate for transplant.

Patient support. This is another big one. This disease requires a lot of education and a lot of time sitting talking with your patients about what the disease is, what the treatment options are. You know, having that shared decision-making about which treatment is best for them. Providing them with resources that they can read up on everything. Getting insurance coverage and navigating the cost of these medications.

We again take a multidisciplinary approach. We have great pharmacy support and a coordinator that helps to get these medications approved and covered. There are lots of grants and patient assistance programs that can help with the coverage as well if their copay is still very high. Most of our patients end up having a zero-dollar copay after we get all those patient assistance programs and support set up for them.

And then again, optimal patient care across the multidisciplinary team. Get electrophysiology involved. If you have concerns about ALl get your Hemo team involved. Neurology if they are having a lot of peripheral neuropathy. Pharmacy, nursing. It is a team approach, and that is really the best way to manage these patients.

Unanswered questions. So what is the long-term safety of TTR depletion? We really do not have a good answer to this yet. I think we will have some more information as these drugs are out for longer.

We are monitoring for ocular side effects. Supplementing with vitamin A with some of these therapies like Patisiran. But we really do not know what the long-term effects of this are going to be.

What is the best way to assess for their treatment response? It is a progressive disease. We are able to slow it, but how do you know if you are doing a good job or not? Again, going back to 6-minute walk is a great objective way to get that data. If you have it, get a cardiopulmonary stress test. Monitoring for more arrhythmias. Watching those biomarkers like NT-proBNP and troponin to see if that is trending up or holding steady. Those are all really great ways to monitor their response.

Therapy initiation switch. There was a good consensus update that came out recently that has a fantastic flow for basically how to choose which therapy is best for your patients. I think that is really helpful, keeping in mind do they have both peripheral neuropathy and cardiomyopathy. You may want to choose vutrisiran in that case. If you are just treating cardiomyopathy and the patient does not want to come in for injections, or they do not want to do injections, maybe one of those oral therapies is better. I know I have had a lot of trouble with especially these 88-89- year-old patients who want to be left alone. Having them come in for injections every few months is not something that they really want to do. Having that shared decision-making is another great tool.

Treatment in presymptomatic patients. That is more of a tough sell for you as a clinician trying to get them on an expensive medication with potential side effects when they feel fine. I have patients telling me all the time, "I do not have any heart problems. Why are you doing all these tests and starting me on these expensive meds?" If we find that their PYP is positive, they have positive genetic testing, they have that diagnosis.

If we diagnose it early and they are not symptomatic, that is the best time to start treatment. That is when they are really going to get the maximum benefit from these medications. Because we are slowing the progression of this disease. We have not found a way to halt it completely or reverse it.

What do we do with ATTR variant gene carriers? Maybe they had genetic testing for other reasons. They did 23andMe, and they come to you saying, "Hey, I have this TTR gene that came back positive. What do I do?" You can do the workup, get an echo, get a PYP scan, genetic testing, labs. If all of that is completely normal and they are not showing any signs of disease, then we typically will just monitor these patients. We will get an echocardiogram yearly or sometimes alternate an echo with a PYP scan. Then some of it is also reassurance and education, going back to penetrance. Just because they have that mutation does not necessarily mean they will develop that disease later on in life.

Dr. Giaconoa: Thank you so much for your insights, Gabriel. I really appreciate it. I am sure we all have benefited and learned a lot.

[01:02:01]

With that, we will move to our skill building number 2.

[01:02:07]

As always, we have another patient case. This is Mr. Daniels, a 69-year-old man. He says, "Just tell me like it is." Mr. Daniels was recently diagnosed with wild-type ATTR cardiomyopathy. Initially, his symptoms were mild dyspnea and neuropathy with a history of carpal tunnel pain. He is analytical, values honesty, and he just wants to understand his treatment rationale.

Therapy-initiated diagnosis was diuretics, low-dose beta blocker, and tafamidis. He is very overwhelmed. He says, "I do not understand. Does this medication fix my heart, or is this how it will always be?"

[01:02:51]

For the audience, which response demonstrates the best communication approach?

1. "Tafamidis usually helps patients feel noticeably better within a few weeks, so you should expect symptoms to improve soon."
2. "ATTR cardiomyopathy is a progressive condition, and we cannot reverse existing changes, but we can significantly slow further progression."
3. "Unfortunately, there is no cure, and we cannot find the damage that is already done, but we will try to manage things as best we can."
4. "Let us continue the medication and see if anything changes before we get into too much detail. If it helps, great. If not, we can talk more later."

[01:03:52]

So he follows back up in 1 year. He reports increasing fatigue and difficulty climbing stairs. While you are talking with him, Mr. Daniels asks, "So the medication is not helping. Are we just wasting time?"

[01:04:12]

Poll 11. Which response best addresses his concern?

1. "Some of what you are noticing is probably normal aging, and it does not necessarily mean the disease is progressing. Many people at your age start to slow down."
2. "If the medication does not seem to be giving you the improvement we want, we could consider stopping it and trying something else or focusing on symptomatic treatment."
3. "If your symptoms are getting worse, it makes me wonder whether the medication has been taken correctly or whether doses were missed. That is often the issue."
4. "Tafamidis helps slow the disease, but it does not stop symptoms entirely. The changes you are noticing are important."

[01:05:20]

Patient Case 2: Follow-Up at 2 Yr

So we go another year, follow up at year 2 with Mr. Daniels, and he reports now that he is experiencing dizziness, constipation, and worsening neuropathy. He asks you, "Is this still my heart problem, or am I getting a new disease on top of it?"[01:05:38]

Poll 12. Which response best supports his understanding of his condition?

1. "ATTR cardiomyopathy can affect more than the heart. It can impact nerves and blood pressure regulation too."
2. "Everything you are describing is typical for ATTR cardiomyopathy. They are just part of the condition."
3. "At your age, symptoms like these are common. It is hard to know what is your ATTR cardiomyopathy versus regular aging."
4. "These symptoms may feel uncomfortable, but they are not dangerous. So try not to focus on them too much."

[01:06:44]

So now I will call upon our incredible faculty to come back and join me, and I will prompt them with what are some questions from patients that you typically see? And what we can start with what has happened to this patient over the years, how would you guys have approached this patient, and what are some important points that we all can learn, and how to address this in our own patients?

Gabriel Dascanio: I think one of the biggest questions that I guess I get is, you know, what happens 5, ten years from now? You know, what is the progression of this? And how do I maintain my quality of life? That is really the biggest one that I get. And, you know, having that discussion with them about it being a progressive disease, that we can slow it, but we cannot halt it. You know, letting them know some of those red flag symptoms, what are some of the symptoms they could expect, and how to best manage those symptoms.

I think giving them the power and knowledge really makes your job a lot easier, because they will come to you if they are having problems, and you can start treating it earlier. You know, especially like with volume overload. If they can come to you before they have to be in the hospital and be diarized, you know, 15-20 pounds, and you can just change their diuretic regimen, it is a lot easier to manage.

If they start developing neuropathy, you can get them in with a neurologist. If they have dizziness, maybe AV block, you can get them in electrophysiology sooner. Just the early recognition, so you can try to manage it and preserve their quality of life as best you can.

Jill Waldron: Yes, I like that. I think that is my number 1 question too, is about prognosis. A lot of times they want to plan ahead, and a lot of times they are not afraid of death necessarily, but they want to know what it is going to look like at the end. They want to know how long they are going to be around, so they can plan financially if they need to move closer to other family members.

A lot of times also they are really amazed to find out that it is not just a heart condition. A lot of times they will start out with a cardiologist somewhere else before they come here, and they will get on treatments, and they will find out about their heart failure, but then when we talk about how neuropathies, and hip pain, and shoulder pain, and back pain, and all of those things could be related, and oftentimes really are, they are surprised.

And so then once they learn that, then they start asking wellness questions, and what kinds of things can I do to be better? Will exercise help me? Will it make it worse? And we talk a lot about exercise, actually. Sometimes I tell patients that amyloid is like a tin man syndrome, that it makes everything stiff. It makes your heart stiff. It makes all your joints, and your bones, and everything stiff, but lubrication for them is movement, and that they need to move every day, and not just for their cardiovascular, for the big vessels in their heart, but also stretching, and stretching all the small things, even their hands, because they get older, and they cannot use their silverware.

And so it is interesting how the questions change over time. They start out with wanting to know prognosis, wanting to know how to plan, and then once they come to terms with that, then they start asking questions about how can I have my best quality of life? How can I live longer with this? What do I need to do to minimize symptoms and be preventative? And I love that actually about this patient population, because even though they are older, they really want to have treatment.

And when I first started, it seemed like there were a lot of myths that, "Oh, they are older. They do not need treatment. He just got diagnosed at 90. Do I really need to put him on this expensive medicine?" But like you said, most patients do not pay much at all, and it is on Medicare now, on formulary, and we can find something. Even if everything went wrong, we can find a trial. We can find some treatment for you. But if you do not treat these patients, even that 90-year-old who has been doing so well for so long, within 18 months, it can be the difference of them standing upright versus being hunched over. And so questions of wellness are a big one too, and then really a lot of education and reassurance, like you said. Yes.

Dr. Giaconoa: Excellent. Excellent. Thank you both.

So we do have some Q&A at the end, so I will move through some polling questions with the audience, and then I will pull you guys back for a good Q&A session to wrap us up.

[01:11:48]

So I will move to the reflection part for this section, commitment to practice change from the audience.

[01:11:56]

Poll 13. How likely are you to incorporate shared decision-making conversations with patients as their ATTR cardiomyopathy progresses?

1. Not likely;
2. Slightly likely;
3. Moderately likely;
4. Very likely; or
5. Extremely likely.

[01:12:44]

Poll 14: Take a moment to reflect on what this case brought up for you. What is one area you would like to improve in your communication with patients who have ATTR-CM?

Moving to our next poll. Take a moment to reflect on the case brought up for you. What is one area you would like to improve in your communication with patients who have ATTR cardiomyopathy?

1. Clarifying the goals and limits of treatment;
2. Discussing prognosis and future expectations in a compassionate, honest way;
3. Responding to emotions such as fear, frustration, or grief;
4. Engaging in shared decision-making;
5. Communicating with family members or caregivers and facilitating difficult conversations;
6. Checking for understanding and health literacy;
7. Coordinating messages across the care team so patients receive consistent and aligned information.

[01:13:48]

And before we do our posttest, some take-home points for us all to remember.

ATTR cardiomyopathy is more common than previously recognized and often misdiagnosed. There are a lot of mimics that were talked about. We need to be focused on early signs and early diagnosis. That is critical, right, because disease-modifying therapy is available.

Recognizing those red flags can help us ensure timely evaluation. Non-biopsy diagnosis is possible and should be used. Treatment requires a multidisciplinary approach and ongoing management, consistently checking in with our patients.