Talking Tall Rounds: Post-diagnostic Monitoring of Cardiac Amyloidosis

Podcast Transcript

Announcer:

Welcome to the Talking Tall Rounds series, brought to you by the Sydell & Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Mazen Hanna, MD:

Good morning, everyone. This is a Tall Rounds, that's the third of the amyloidosis series. So last Fall we did a Tall Rounds on the diagnosis of cardiac amyloidosis and did a deep dive into that. This past Spring, the second series was on the treatment of cardiac amyloidosis. Today, this third series is, after you've made the diagnosis of cardiac amyloidosis, how do you follow these patients longitudinally. I do want to thank this educational grant for partial support of this activity, Alexion Pharmaceuticals, Alnylam and AstraZeneca Pharmaceuticals for making this possible. We're going to start with a case presentation. Our fellow Dr. Alvin George, who's a fellow in heart transplant, will present this case.

Alvin George, MD:

So this is a pretty typical patient that we actually see in our clinic. This is a 77-year-old African-American male. He was seen as a consult for heart failure in 2018. He has a past medical history of well-controlled hypertension, heart failure with a diagnosis of hypertrophic cardiomyopathy at this time, paroxysmal AFib, as well as bilateral carpal tunnel syndrome, spinal stenosis. Review of systems is negative for peripheral neuropathy. His vitals are within normal parameters on these medications listed here below.

This is just a snapshot of the parasternal long axis on his echocardiogram. We can appreciate some asymmetric septal hypertrophy here with the dimension of 2.0 centimeters as well as a posterior wall thickness of 1.3 centimeters, something typically we would associate with hypertrophic cardiomyopathy. His initial echocardiogram showed sinus rhythm, PAC, some low voltage in the limb leads and prominent voltages in the late lateral leads without formally meeting criteria for LVH.

This is his apical four-chamber view, so you can appreciate the LV hypertrophy here as well as biatrial dilation. His mitral inflow demonstrated a grade 2 pseudonormal filling pattern and we can also appreciate a prominent L wave here as well. Based off of these studies, an amyloidosis evaluation was initiated and that was started with a light chain survey. His kappa lambda ratio was just a bit over the normal limit, but normal nonetheless. He did not have a M protein spike on immunofixation. His biomarkers were notable for an NT-proBNP of 3,100 and troponin of 0.035 and creatinine of 1.4 with a mildly reduced GFR. PYP scan demonstrated grade 3 uptake and SPECT imaging also showed diffuse myocardial uptake as well. He underwent genetic testing and that revealed a V122I variant, and he was diagnosed with hereditary ATTR amyloidosis or also known as transthyretin cardiomyopathy. At this point, we're often faced with three questions in particular. What is the prognosis of this pathology? What are the treatment options that are available and how do we go about monitoring this patient?

Mazen Hanna, MD:

I'm just going to give a brief ten minute big picture just to reframe where we are. Remember, the two most common types of amyloidosis that affect the heart are AL or light chain amyloidosis, which is a plasma cell clonal disorder or the much more common type transthyretin or ATTR amyloidosis in which the liver derived protein transthyretin is what's leading to the amyloid fibril. So this is the focus of today's Tall Rounds. Remember, when the fibrils deposit, they deposit throughout all the myocardium, atria, ventricles, conduction system valves, stiffening the heart and ultimately, causing a variety of clinical presentations, most commonly heart failure, but arrhythmias sometimes looking like hypertrophic cardiomyopathy like you just saw in the case presentation. So when we diagnose somebody, that first visit in the office, it's actually very anxiety-provoking for the patient. When they see the word amyloidosis, what do they do? They immediately go to the internet and a lot of outdated information about survival is in the internet. There is an old paper that says that when you get diagnosed with cardiac amyloidosis with heart failure, you have six months to live. That was in the context of AL amyloidosis, and that's very far from the truth even in that particular condition.

The current prognostic staging systems, there were three that were developed, one from the Mayo, one from the National Amyloidosis Center in London, in the middle, and then the Columbia staging system added a little nuances. So in the Mayo staging system, they look at troponin T and NT-proBNP. If your NT-pro is less than 3,000 and your troponin T is less than 0.05, you're considered stage 1. If one or the other is above that threshold, you're stage 2, and if both are above that threshold, you're stage 3. The UK staging system is a little more practical in that it just relies on NT-pro and estimated GFR. And the cut-offs are again, NT-pro 1,000 and a GFR less than 45. So if your NT-proBNP is above 3,000 and your GFR is less than 45, that would constitute stage 3. Now, what the Columbia group did is they looked at a cohort and showed that New York Heart Association class and diuretic dose added to the staging system as far as predicting outcomes. Basically, you get points for what UK stage you're in, and then you add the NYHA class and then the degree of diuretics you're on. We all know that the higher the diuretics, the sicker the patient. So there you can see the staging system. In general, if you're stage 1, your survival's about five to six years, stage 2, about three to four, and stage 3, about two years.

But what's extremely important is these staging systems were developed in the pre-treatment era. When you're sitting in front of a patient and you're saying, "Well, this is what your predicted prognosis is." I tell them, "That this really doesn't hold water anymore. This is more natural history. Now that we have treatment, this is completely incorrect." Remember, that as far as the treatment, we've been able to by understanding the biological underpinnings, knock down production of TTR by the liver, stabilize the tetramer, and now a couple antibody studies that we're involved in to try to actively remove the heart.

Now, full disclosure, still the only FDA approved drug for this condition is Tafamidis, in the middle there. It stabilizes. It's an oral drug that stabilizes the tetramer and is meant to slow down the progression, best-case scenario, stabilize the patient. So when you're sitting there and telling them about the diagnosis, you say, "This is a medication that's been FDA approved since May of 2019." And you have to have the conversation that, "This likely will slow down your condition, best-case scenario, stabilize it, but it's not going to reverse what's already there." The patients always say, "Well, how do you know it's working?" I tell them, "The only way to know it's working is to clone you, give your clone a placebo and give you, for the next five years, Tafamidis. Even if you progress, you probably are going to progress a lot more slowly than if you weren't taking the medicine." Recall that this trial for Tafamidis was published in 2018, showing a very significant mortality benefit with a number needed to treat of seven to eight patients over two and a half years.

The patients who enrolled in this trial were sicker, average NT-pro 3,000. Many of you now are diagnosing these patients with NT-pro's in the 1,000 range because of better recognition. Remember also, that in the trial, they looked at six minute walk and KCCQ quality of life score. Even in the Tafamidis arm, still at the end of two and a half years, the six minute walk decreased by 50 meters so the KCCQ also decreased on average. Now, obviously on placebo it decreased a lot more, so you're slowing down progression, but again, you have to prepare patients for this potential. If you look at the echo parameters over time in a post-hoc analysis of that study, even the Tafamidis arm still decreased EF mildly, decreased stroke volume, and a little bit worsening strain. Obviously, better than placebo, but we don't expect the echo to get better. How do you assess disease progression once you put patients on this medication? Three ways, you look at the patient, you look at biomarkers, and then you can look at imaging and you take that constellation and tell the patient you're stable or maybe you have mild progression.

The patient in the office, you're asking them what they can do, you come up with an NYHA class. We don't do routine six minute walk tests every six to 12 months. I just talk to the patient. Some people advocate this. For me, it doesn't necessarily change management, so I don't do it. But diuretic dose is something I pay attention to. Now that we have SGLT2 inhibitors, oftentimes these patients may not even need a loop diuretic. But the more loop diuretic they need, the worse off they are.

Have they been hospitalized? Obviously, that's a marker of progression. Have they gone into AFib? I'm not sure that's a marker of progression because the nidus is there to develop AFib, so it doesn't necessarily mean you've progressed, but we look for those kind of things. This is a paper from the NAC about the prognostic value of six minute walk. In short, basically the lower your six minute walk is at baseline under 350 meters, the worse your prognosis is. If you worsen over 35 meters and one year or by more than 5%, that's increased hazard ratio for mortality. Makes sense.

The other thing that we look at is outpatient diuretic intensification. You'll see this term called ODI, it's all over the place now even in HFpEF trials, because we all know that when you have to gradually increase the diuretic, that patient is getting worse. This particular paper looked at outpatient diuretic intensification at various levels versus none and the worst survival were those where you had to increase the Lasix more than 40 milligrams. Again, a marker of worsening survival. When you combine that with NT pro BNP progression, and this paper was greater than 700 or more than 30%, you can see that the hazard ratio is significant. So the combination of NT pro BNP progression, outpatient diuretic intensification, portends a worse survival. We talked about the patient. We talked now about biomarkers. Again, the NT pro BNP really fluctuates. Patients freak out when it goes from 1,500 to 2,100, and that could be because they had two slices of pepperoni pizza the day before. So you follow that every six months and you look at a trend and oftentimes it'll bounce around. I try to tell them not to look at it to the letter of the law.

Now, prealbumin, you can order prealbumin levels. And guess what, pre-albumin is transthyretin, it just never changed the name. A normal level's 20 to 40. When you give a stabilizer, the level goes up by six or seven. So sometimes as a poor man's way of looking, is it stabilizing, I'll look at a prealbumin level.

Just to finish off, the third part, and you can see I didn't focus on this much, is looking at the imaging. Often these echoes don't really change that much. You can look at the ejection fraction, the wall thickness, the diastolic function, the LVOT VTI, look at the valves. In general, I don't get this more than once a year. The patients really want it, but oftentimes it doesn't give me tremendous information. Repeating a PYP scan over time, right now is not validated. We don't do that. We have seen regression in the uptake, but we don't really know what that means, so we don't do that. Cardiac MRI, Dr. Kwon's going to talk about that in more detail. It's a really interesting tool to be more quantitative about what's happening. There's some very interesting PET agents that also can be quantitative.

Just a quick mention, this is unpublished data. We looked at wall thickness measurements, and just to note that inter- and intra-observer wall thickness variability is significant. I don't tend to pay attention to the reports. I look at it, but again, it's not strikingly important. So just to end here, that 77-year-old African-American male with a hereditary ATTR cardiomyopathy that Alvin just presented, who presented in April, 2018 with an NT pro of 3,000. He was about NAC stage II, predicted survival of three years because of his V122I. Yet, we were able to get him on these other medicines we used to use. When Tafamidis became available in the extended access program, we got him on that in October 2018. Then it was FDA approved, he went commercial. Then we enrolled him in the HELIOS-B trial, which randomized him to Vutrisiran, which is a silencer versus placebo. Then he got in the open-label extension, he's been getting drug for over a year and a half. And here he is over six years later, NYHA II, NT pro 1,550, EF in the 50, stage II diastolic function. This gentleman's lived six years, and quite frankly, I think his trajectory could be another six years. This is what happened to his NT-pro-BNP over time. But at the end of the day, although we're diagnosing people early, middle, and late, the fact that we have treatment now, we can monitor progression and now potentially regression. So with that, I'll introduce Dr. Kwon who will talk about cardiac MRI as a tool to monitor these patients.

Deborah Kwon, MD:

Thank you for the opportunity to talk about cardiac MRI and how this can be used to assess progression and treatment response. As we all know, CMR, it provides very comprehensive phenotyping. It gives you this vast array of really synergistic imaging features going from gold standard LV size, mass and function. We can also provide strain, myocardial perfusion, flow, atrial mechanics and then most importantly, tissue characterization with T1 mapping, ECV mapping and late gadolinium enhancement. All of these imaging features get very interestingly impacted by amyloid deposition. I also just wanted to provide this diagnostic imaging algorithm that there's two different guidelines with ESC AHA. I'm not going to go into this into detail. We often focus down here in the diagnosis, and CMR has somewhat of a limited role, but in this paper recently published, CMR is actually up here as a modality when you're looking at patients who have clinical red flags, shortness of breath, LVH. You're not quite sure yet what the diagnosis is. CMR is an important modality to rule out other causes of LGH such as hypertrophic cardiomyopathy, Fabry's, et cetera.

So CMR does have a role upstream potentially in patients with shortness of breath. In terms of prognostic imaging features, amyloid is just such a fascinating disease entity in terms of imaging because there's so many different imaging features from nuclear, echo, to CMR that manifest and help us diagnose this disease. In terms of prognostic assessment, CMR really provides a lot of important features in terms of thickening of the myocardium systolic function, stroke volume, strain, LGE, T1 mapping, and ECV. Really, this gives you a very comprehensive assessment of what's going on with the myocardial substrate. In terms of findings in amyloidosis, I just wanted to highlight that in a cine image, you can have very similar degree of LV thickness, but actually the degree of amyloid deposition within that thickened myocardium can be very different. In patient A, you can see there's a thickened myocardium, which looks very similar to patient B. However, the T1 mapping is quite different. Patient B has a significantly higher native T1 time. You can look at the LGE, you can see there's definitely more LGE deposition or enhancement in patient B. ECV mapping is 62%, normal is 28 to 29%.

This patient above also has elevated, but you can see patient B is significantly more. You can also see on the perfusion map that the perfusion in patient B is definitely almost half the patient A. But if we go back to the morphologic features, just in terms of LV thickness, which you could see by echo potentially would be very similar. In terms of TTR amyloidosis, definitely PYP scan is the imaging modality that helps us diagnose the patient. But this was a really interesting study from the UK demonstrating that if you just look at grade 0 and grade 1, there's actually a lot of different phenotypic imaging features that you can see with CMR. Focusing just on grade 1, these are the different degrees of LGE enhancement that can be seen in a grade 1 PYP scan. So going from no LGE, all the way to very diffuse LGE. This really provides you further phenotypic assessment in a patient with grade one PYP scan.

In terms of imaging characteristics, this is a study that demonstrated regression versus progression. As Maz had highlighted, with echo it's very hard to see small changes with treatment. Probably the best imaging feature on echo is strain. So the strain can potentially show that it's improving with regression versus not changing or getting worse. But again, it's very difficult to tell from patient to patient. This is in contrast to CMR. So you can see with CMR with the LV thickness, you can see a little bit of regression, but it's very striking actually, when you look at T1 mapping, LGE and ECV. This is a patient that had diffuse LGE with treatment, you can see very striking regression. This patient, unfortunately, did not respond to treatment, and you can see that there was not that much LGE to begin with and striking progression over time. Again, in this patient with progression, there was not that much increase in LV thickness that you could see with echo.

This was some other studies demonstrating CMR's ability to look at treatment response. Regression with cardiac amyloidosis has been seen with AL amyloidosis with chemotherapy as well as with Patisiran for ATTR. In 42% of the patients there was a decrease in LV mass. Again, because CMR is a gold standard and allows very precise measurements for LV mass, you can actually quantify this and see this with a smaller number of patients, so decrease in LV mass, decrease in LV volume and decrease in ECV with significance. ECV increase also correlated with decrease in biventricular function and increase wall thickness. Again, these are very striking differences in terms of late gadolinium enhancement from baseline to follow-up and this is a very striking response to treatment.

Okay, what about change in ECV? This is probably our best quantitative measure by CMR. LGE is very easy because just when you see it, it's present or absent. But actually getting quantitative assessment with LGE can be a little bit tricky because of changing gadolinium kinetics and creatinine in these patients. Quantitative ECV is probably the most quantitative imaging feature that we can look at.

This is a study in patients with AL amyloidosis and TTR amyloidosis, and they looked at ECV volume stabilization or decrease versus increase in ECV volume. This quantitative assessment during treatment demonstrated that if you stabilize the ECV or improve the ECV, these patients have significantly improved prognosis compared to those who have progression of ECV. This is really a nice tool that we can tell patients how you're responding to treatment.

This study was very interesting to me because ECV requires contrast administration. In this study, they looked at native T1, which does not require contrast, so this potentially could be done without contrast in a shortened study. They demonstrated that patients who have decrease in T1, so that's getting better, had significantly improved survival compared to those who had increased in T1. You see those patients with increased T1 at six months, so this is at a very short time interval, you can see a very striking separation of curves in terms of prognosis. Again, this can be done without contrast.

This is a really exciting study to see that with a non-contrast CMR, you can get a lot of information both the LV mass function and native T1. Okay. This was a recent study that was presented at ACC looking at Acoramidis and again, demonstrating that you can see improvement in LV mass, stroke volume, EF, strain, ECV, and also RV function with this second generation agent. It's also a stabilizer. But I thought this was really interesting. So as Maz pointed out, this is a slow progression. So in patients with sustained amyloidosis progression, this is over 30 months. You can see the increase in ECV is on the order of 2-3% each year. In terms of stability, it was really stable at 12 months, then only at 24 months do you start to see regression at 64, then 58. Really, it takes a while in many patients to actually see a response and decrease in ECV.

And lastly, I just wanted to point out this really interesting study that looked at CMR to look at multi-organ cardiac amyloidosis response. The nice thing about CMR is you don't only look at the heart, you also see the liver and spleen in the field of view, and you can do T1 mapping and ECV in these organs as well. Basically, they demonstrated that if you have a regression of amyloidosis, you can see a stark drop off in the amyloid deposition, particularly, if you see a drop off in the liver and spleen because these are the organs that produce and cannibalize the amyloid fibrils, if you will. On the other side, on the contrary side, if you have increase in amyloid with progression, you can also see this in the liver and spleen as well. So it's a multi-organ problem, obviously, but with CMR, you can evaluate all of the organs in the field of view, which I think is very interesting.

So just quickly to say that, I think that it's really exciting to see AI coming into the field. I think this will greatly enhance our ability to diagnose, but also predict outcomes and potentially predict which patients may respond better to which agents. We have the multi-imaging data that we can collect here. There's really interesting things that we can do with radiomics and different convolutional neural networks. And this can allow us to really get to precision medicine for our patients.

So in conclusion, CMR plays an important role in characterizing the extent of the disease, which provides important prognostic implications. CMR enables precise quantitative measurements to assess interval regression versus progression of cardiac and multi-organ amyloidosis deposition. With multiple therapeutics on the horizon, CMR may emerge as an important imaging modality to enable patient-specific treatment selection and treatment response. Thanks so much.

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