This transcript has been edited for clarity.
Michelle M. Kittleson, MD: Welcome to Medscape InDiscussion: Heart Failure. I'm your host, Dr Michelle Kittleson. This is the seventh episode of our 12-part series. In the second half of the series, we're dealing with special concerns, and today we'll talk about cardiac amyloidosis: What are the red flags and pitfalls in making an accurate, timely diagnosis? What about treatments for transthyretin (TTR) amyloidosis? What will the future look like for expert guidance on these questions? We've invited Dr Mat Maurer. He directs the Clinical Cardiovascular Research Laboratory for the Elderly at Columbia University in New York City. He also directs the Cardiac Amyloidosis Program at the New York Presbyterian Hospital, Columbia Campus. Welcome, Mat. I'm so happy to have you here.
Mathew Maurer, MD: Thank you so much. I'm very excited to talk to you today about amyloidosis, one of my favorite topics, obviously.
Kittleson: Speaking of being one of your favorite topics, you have achieved the holy grail of academic medicine, where your name is synonymous with expertise and a clinical condition — in this case, cardiac amyloidosis. In fact, I think you were interested in amyloidosis back when most clinicians were fatalistic about a condition with few treatment options. Cardiac amyloidosis has undergone a renaissance in the past decade. I'd love to know what inspired your initial interest in cardiac amyloidosis and what keeps you engaged today.
Maurer: Great question; I think the latter is easier. What keeps me engaged is the patients. They're just lovely, wonderful people whom we all have the privilege of taking care of, but they are really a special group of individuals. The question about engagement is a little more difficult. I'm maybe not the brightest person, as Milton Packer once said, but I'm the most persistent. He hired me in 1999 for what was one of the first heart failure programs in the country. Jokingly, he said, "Everyone's doing systole, so why don't you go do diastole and relax?" And those individuals in the country who specialize in the clinical syndrome of heart failure with preserved ejection fraction (HFpEF) are much smarter than me and were able to embrace a lot more of complexity, I would say.
But I, fortuitously, began to see patients early on who had cardiac amyloid, was intrigued by the pathophysiology, and then made a few important connections, working with a guy named Jeffery Kelly. For those who don't know, Jeff invented tafamidis, and he started a company back in the early 2000s called FoldRx. So, we did some seminal work with Jeff: natural history studies, developed a large registry. The rest is history, so to speak, but the motivation remains always the patient. Really, that's what we're here for.
Kittleson: I love that question, because I always learn something new, something I didn't know, and I love the theme behind that, which is if your priority is to take great care of patients, you may not know where the adventure will lead you, but it will lead somewhere good. Let's dive in, so our guests will leave this podcast knowing everything they need to know about cardiac amyloidosis: from diagnosis to treatment to new advances. It's a particularly challenging diagnosis to make because it will not be uncovered on routine testing. You need to know to order the right tests to make the diagnosis. If you don't look for it, you will not find it. Let's start with those clinical clues that should make a clinician suspect that cardiac amyloidosis might be afoot.
Maurer: Yes. It's not that hard a diagnosis to make. We develop these appropriate, if you will, algorithms and protocols, and the key thing is you need to be prepared as a clinician to think about it and be aware of it. One of the misnomers in the field is the idea that this is really a rare condition. The provider's impression is that they're kind of looking for a needle in a haystack, and the available data that are out there suggest, for example, that among hospitalized patients, if you have HFpEF with an increased wall thickness, you've got a 16% chance or some odd of having a cardiac amyloid. If you underwent a transcatheter aortic valve replacement (TAVR), it's a similar percentage. In the community, it's a little less common, about 6%, and is quite commonly mistaken for hypertrophic cardiomyopathy (HCM). So, probably about 5% of patients who have HCM are misdiagnosed and probably have amyloid. In those over the age of, say, 65 or 70 years, it could be as high as one quarter; it's quite common as people age.
The first message is that we're all seeing cases of cardiac amyloid, and all you need to do is start to let it into your differential diagnosis. As we say, "If you don't think about it, you'll never diagnose it." But to your question about the clinical clues, the central phenomenon is that these individuals have an increase in left ventricular wall thickness. We in amyloid don't call that left ventricular hypertrophy. We specifically say wall thickness because it's not hypertrophy; it's not muscle. The clues are numerous. You can have heart failure in an older adult, particularly an older adult male. We mentioned aortic stenosis. Often, these individuals do not have concomitant hypertension. Their ventricles are small; they have a low stroke volume, so their cardiac outputs are low. Over time, though, these individuals become hypertensive, so you're cutting back on medicines.
There is neuropathic involvement in some individuals, either a sensory or peripheral neuropathy. They can even have subtle autonomic symptoms — in men, erectile dysfunction — or gastrointestinal upset. There's the light chain (AL) form of amyloid, which we're probably not focusing on much today, but those individuals have multisystemic involvement, so you can see proteinuria; you can see periorbital purpura. You don't see that in TTR often — in fact, very, very rarely — or a big tongue. In TTR, there are all these orthopedic phenomenon that are just fantastic clinical clues, right? We all know about bilateral carpal tunnel syndrome, but there is the classic Popeye's sign: a ruptured biceps tendon; hip, knee, and joint replacements. Mazen Hanna just reported about shoulder replacements as well. Then there's a whole host of imaging findings that we can touch upon. But the classic phenomenon is low voltage on the cardiogram, or voltage that's not necessarily low but just not in proportion to the wall thickness on the echocardiogram. Obviously, for those who have variant disease, taking a family history is quite helpful, because you can find that out on an EKG. Besides a low voltage, obviously a pseudoinfarct pattern would be another phenomenon. In fact, there are so many clues that it's kind of amazing we don't think about it or see it more frequently.
Kittleson: I love that, and it's a great example of why we are all doctors first and subspecialists later. You don't have tunnel vision on your organ. You can identify these seemingly disparate clinical clues and find a very satisfying, unifying diagnosis. So, say we've crossed the first hurdle. We're thinking about the diagnosis. Now we need to order the right tests. Tell us your approach to a streamlined, accurate diagnosis and the common pitfalls you see in practice.
Maurer: With pitfalls lately — it's a little bit because we've heightened awareness about amyloid. There are lots of people getting tested who may not even have a phenotype that's suggestive. If we start randomly applying these diagnostic tests to people with a very, very low pretest probability, we're going to end up with many false positives, and the positive predictive value is not going to be in a range that's useful to anyone. That's the first thing, and while I'm very happy about people being aware of this, there's a constellation of findings. But it does usually start not only with the history that we talked about in those clues, but on echocardiography or MRI, a phenotype that's suggestive of amyloid. It's an increased wall thickness with a small chamber or a high relative wall thickness. The approach we use is straightforward. First and foremost, you should probably tell the patient what you're thinking about. I think we forget to do that. It's a little alarming for people. God forbid they utilize the internet and they read about amyloid. The first thing that still comes up is a dictum about AL amyloid that's untreated that says they're going to be in a grave in 4-6 months, so that's not a thing you want to leave a patient to find out on their own, in their own home. There's a lot of shared decision-making. For example, you may say, "I'm thinking about this diagnosis. This is what it entails. This is where my thoughts are." That's important, and it's straightforward.
Regarding streamlining, it's really a three-step process. You want to evaluate for AL amyloid, because that is quite malignant. That involves essentially three tests that assess for monoclonal proteins. It's serum protein immunofixation, not just a serum protein electrophoresis (SPEP), but an immunofixation, looking for those small proteins: the kappa and lambda, chains, along with intact immunoglobulin. A urine immunofixation, which can be done on a spot urine; it doesn't need to be a 24-hour urine collection. And then, obviously, the kappa lambda free light chain, which is probably the best biomarker we've ever developed, the reason being it's a biomarker that's diagnostic of the disease. It's a biomarker that's prognostic: the higher the difference between the involved and uninvolved light chain. It's part of the Mayo score, and it's the target for therapy. If only we had such biomarkers in all of medicine, it would make life easy. Those are the three tests to assess for a monoclonal protein.
If someone has a monoclonal protein, then the noninvasive approach to diagnosis off bets. You can't diagnose some AL amyloid without a biopsy, at least not yet, so you need to shift gears and move toward a kind of invasive approach. But for TTR, which is the majority of what most people are going to see. A vast majority, I would say, because of the aging of the population, If there are no monoclonal proteins, then you can get nuclear scintigraphy either a pyrophosphate or a hydroxymethylene diphosphonate scan. Both are available, and if that shows diffuse uptake, that's confirmed by single photon emission CT imaging. It is really important to confirm that you don't have a blood pool as the cause of what you're seeing on planar imaging, then, basically, you've made a diagnosis of TTR amyloid. Now, you just need to genotype the patient. So, the three steps are monoclonal protein assessment, PYP scan, and genetic testing. Pretty algorithmic and straightforward.
Kittleson: I love how you start with "Tell the patient what you're thinking about." Then we need to remember, don't just do SPEP urine protein electrophoresis (UPEP), do the immunofixation electrophoresis SPEP UPEP. If that's not sensitive enough, if the monoclonal proteins are positive, then stop. Do not do your technician scan; biopsy something instead. Call your friendly hematologist and only interpret the technician scan, the bone stratigraphy, in the context of the negative monoclonal protein screen.
Now, let's say we've successfully met the hurdle of accurate diagnosis, and we talk about treatment. When it comes to AL, again, we're collaborating with our friendly hematologists and allowing them to direct therapy against those pesky monoclonal proteins. But what about TTR? Tell us the best treatment for TTR amyloid cardiomyopathy.
Maurer: Hopefully, the best treatments are still to come. Right now, we only have one FDA-approved treatment, unfortunately. That drug is tafamidis. This field is evolving so rapidly because amazing basic scientists like Jeff Kelly have really elucidated the biology. It's very clear: We have a small protein produced predominantly in the liver, and its job is to transport thyroid hormone and vitamin A, hence the name transthyretin. It looks like a four-leaf clover. The protein dissociates into pieces either because of aging or because of variants in the protein, and those pieces basically agglomerate to form amyloid fibril. Once you understand that biology, it becomes almost like a kindergarten story. You can either shut off the protein or can stabilize the protein. We all hope that one day we could maybe do something at the amyloid fibril level. Those are the three big strategies. The one that's been proven to work is tafamidis as a TTR stabilizer. It is a small unfortunately too expensive of a compound but a highly effective one that in the ATTR-ACT trial, it basically prevented mortality and reduced the number of hospitalizations. The numbers needed to treat (NNTs) are quite low: under 10 for both mortality over 30 months and for hospitalizations. It's an NNT of four to prevent one hospitalization in a year. We still don't need to pay a quarter of a million dollars a year for a small pill every day, of course, but that's the standard-of-care approach. Thankfully, for all the bad things about the US health care system, tafamidis is widely accessible and relatively easy to get, although there are still a lot of patients who have significant out-of-pocket costs.
But people still progress on tafamidis therapy. It's much better when given earlier in the course of the illness. We show that in the trial, in which the patients with class III heart failure tended to live longer but spent a little bit more time in the hospital. And that's not how we all want to spend our time; it's like the last place most of us want to be. So, obviously, with the success of tafamidis, there have been a whole host of newer treatment options that we remain very hopeful about, if not highly confident, that they're going to be effective. For patients who have variant disease, for years, there's been a silencer-based therapy option, since 2018, even before tafamidis. That's for patients who have polyneuropathy with or without a cardiomyopathy. But they must have variant disease and a polyneuropathy. The two compounds in that space, which are now three, were patisiran, inotersen, and now, vutrisiran. So three different silencer-based therapies.
Kittleson: We owe so much to you Mat, being the person who spearheaded the ATTR-ACT trial, and I cannot emphasize enough what you said. Number one: The earlier you start it, the better patients will do; it doesn't reverse disease, it only prevents progression. Number two: Those survival curves take a while to separate. So if you want to give your patient the best chance of doing well, start it as soon as possible so they can start to accrue benefits. And now, we're going to move on to prediction time. I want you to tell us, where we will be in the next decade. Will we be screening communities at risk? How will we be treating asymptomatic carriers? What will be the algorithm for silencer plus or minus stabilizer therapy for our patients?
Maurer: Those are great questions. I'm convinced that there'll be some type of guidelines, if you will: a screening or active ascertainment approach. We don't know what the best one is. I mentioned the false-positive rate, but there are a whole host of approaches looking at people who've gotten carpal tunnel surgery, examining the tissue, and finding amyloid. It is the same as we're doing now for a multicenter study. This has been recently published in JACC by Finn Gustafsson's group in Denmark. They showed that you can identify people much earlier in the course of the illness when you were thinking about it and really going out and looking for folks. We have a screening program with Frederick Ruberg that's focusing on minority populations because they're disproportionately afflicted by the Val122Ile variant, which affects individuals of West African ancestry. That means individuals in the US who self-identify as Black or Caribbean Hispanic. Obviously, there are a lot of health disparities. We must be appropriately active in the idea that as medicine gets more precision-based, we want to make sure no one is left out, so that's why Rick and I have been committed. They'll be an active ascertainment, and we'll have to figure out what the best approach is; we don't know. There'll be a whole host of new therapies. We're kind excited about a new tafamidis called acoramidis. It'll be reporting out later this year. All the silencers I mentioned, including some new ones, such as a drug called eplontersen, which is a subcutaneous silencer, are being tested in large studies. There's even one that's being tested in 1400 patients, which is kind of unbelievable for amyloid.
Most of us believe that these drugs will be effective at obviously knocking down or shutting off the production of transthyretin, which will translate into clinically meaningful outcomes. Patients want to live longer, feel better, and function better. We're hopeful for all those. The "pie in the sky" that people are talking about, even in patients who unfortunately are still diagnosed too late, is whether any anti-amyloid therapy would be effective. There are three or four different companies that are conducting early-phase studies, in which there are kind of monoclonal antibodies that are active against an epitope of amyloid-activate macrophages, like a Pac-Man: just chew up the amyloid that's disrupting the structure and the function of the organ. This is an exciting space, and there are lots of amazing scientists. The collaboration among investigators around the country and junior faculty is great. Most importantly, the patients are just all, like I said, not only lovely but also very engaged and easy to take care of. Almost all of them, about 85%, whom we approach enroll in a trial. It just makes the life of a clinical investigator like me very easy.
Kittleson: I love it. I think we've taken our listeners now on a whirlwind tour through the following: Should you heighten your clinical suspicion? How do you make the right diagnosis? What's the right treatment, and what can we look forward to? Tell me, what's the one thing you want listeners to do differently after hearing this discussion?
Maurer: I think it's back to the first point, which is to put amyloid on your differential diagnosis. You've got to think about it to diagnose it. Every time you see someone, think about whether this potentially is amyloid. That's the main starting point for clinicians and for patients to benefit from all these therapies.
Kittleson: I love it. What we've learned today is: (1) If you follow your passion and make patient care your priority, you will have a fulfilling career in medicine, (2) have a heightened suspicion, as Dr Maurer so beautifully told us, and (3) order the right tests. Don't forget that you can't diagnose TTR amyloid with a positive monoclonal protein screen and a positive technician scan. If your protein screen is positive, then you must biopsy something, and tafamidis is our best treatment for now. So thank you, Dr Maurer, for being here with us today. It's been so much fun to talk to you.
Maurer: Thank you. Your enthusiasm is always wonderful, and your expertise in translating what sometimes is very complicated information to providers is enviable to everybody.
Kittleson: Well, I did not pay him to say that. I will say that Dr Maurer is one of my favorite people in the world — and not just because he answers my emails almost before I send them.
Thank you for joining us today. There's much more ahead in the coming episodes, so be sure to check out the Medscape app, and share, save, and subscribe if you enjoyed this episode. I'm Dr Michelle Kittleson for Medscape InDiscussion.
Resources
Transthyretin Cardiac Amyloidosis: A Cardio-Orthopedic Disease
Low QRS Voltages in Cardiac Amyloidosis: Clinical Correlates and Prognostic Value
What Is New in Diagnosis and Management of Light Chain Amyloidosis?
Comparison of Different Technetium-99m-Labelled Bone Tracers for Imaging Cardiac Amyloidosis
Transthyretin-Related Amyloidosis Treatment & Management
Transthyretin-Related Amyloidosis
Tafamidis Treatment for Patients With Transthyretin Amyloid Cardiomyopathy
Two Decades of Cardiac Amyloidosis: A Danish Nationwide Study
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Cite this: Only Three Steps for Diagnosing Cardiac Amyloidosis? - Medscape - Jun 08, 2023.
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