Chapters Transcript Video Cardio Oncology & Amyloid Primer Dr. Zachary Tushak discusses physiology of cardiac amyloid and reviews treatment plans for identified patients. Yeah, thank you very much for having me. So, my talk today is entitled cardio uh Cardiac Melis and cardio oncology, primer new fields with an old disease. So I have no disclosures. The agenda today is going to be reviewed and to build on our last session last year's lecture. Uh We're gonna review what is Emily Dos, the path of physiology, how it's diagnosed. Uh We're gonna revisit old cases. We're gonna talk about treatment dos and don't. Uh what's new in Emily dois what's cardio oncology, common offending agents and with cases. So what is it? It's an extracellular deposition of toxic mix folding protein. There are two really main, four main types of amyloidosis involve the heart A amid dois which is a hematologic condition. A a amid dois which is a secondary amid dois due to inflammation isolated at amid dois. But what I really focus on what we focus on our clinic is TT R amli dos. So TT R stands for transthyretin. It's a temer that's made by the liver and it actually stands for transports thyroxine and retinol and TT R Emsis. It's a systemic disease that's caused by one destabilization of that temer into uh unstable monomers two and then it then misfolds three and aggregates into insoluble fibers four and then that deposits within the tissue themselves. So once it, it deposits within the tissue, it causes uh manifestations of the disease in the heart, it can cause diseases like dys dysfunction that eventually progresses to restrictive physiology, followed by systolic failure, uh conduction abnormalities including atrial fibrillation and disease like uh a work stenosis, especially if it's low flow, low gradient in the nervous system, it can deposit and cause perier neuropathies. What we think about commonly are involved the hands and feet like carpal tunnel syndrome and spinal stenosis. Uh and then it can also affect the autonomic nervous system, which are things we don't commonly think about. Those include orthostatic hypotension, meaning patients are often intolerant of blood pressure medicines or GDMT postprandial diarrhea, alternative constipation, gastroparesis, urinary retention and incontinence as well as erectile function. And then other manifestations include bicep tenant, ruptures, early renal disease and hepatic disease. So, there are two types of TT R MDOS. The wild type formerly called C now and the hereditary type that run in families. So for wild type is the UN form, it's often connected to advanced aging and is is more common than the hereditary variant. The hereditary variant is um familial, it's automa dominant in its um inheritance pattern. And so that really means that you only need one of the copies to cause disease it stems from 100 potential uh mutations of the TT R gene itself. And uh the most common variant is called A V 142 I is uh involved when A, is uh substituted for is, and it actually affects 4% of African American. 4% of them are geno positive. Um There are a number of other specific mutations that are associated with other ethnicities and um nationalities and they may have a, a varying amount of uh neuropathic or cardiac uh uh diseases and symptoms. So, why is it important? So, it's considered a rare disease but it's really not that rare. Um Doctor Redfield, a Mayo did a study where they investigated uh patients referred for he of those patients, they found that 24% of them had underlying type amid dois as a cause of the he uh an autopsy is 25% of octogenarians actually had under had a wild type amys that was seen in their heart. And then further, uh you know, our center is, is very big into ver. Um there have been a number of studies that have come out in this study. They found that 14% of their patients that were undergoing tar actually had underlying wild type amyloidosis. Uh Another study that was done at my own Institute of UP MC, um also found that 16% of their patients undergoing tar evaluation had underlying amys and there's a high association with low flow of the ingredient and that was taken further. Uh and 16% again, was found of these patients, 78% of their total low flow low gradient patients with a S had amyloidosis. And in this study, they used a cardia MRI to calculate the extracellular volume to determine the significance of the disease. Uh that was taken further uh in this study. And they found the same amount of patients with amy doses. But this time, they used a AC T package where they, they were able to use a uh quantification of extracellular volume to screen for amli doses. In the previous studies, all those patients underwent P IP scans in this study, they use the same CT, they used to uh for the work up. They just add on this extra package and they were able to define those as accurate as screening for amy doses as P IP scans. So, you know, in, in our, in our uh institution, we do approximately uh we've done approximately 500 you know, while we have definitely changed the outcomes in those patients, about 75 of those patients could have benefited from uh further mids evaluation. Um So who should be screened really any intersection of patients with PFLVH eric stenosis, especially those with low flow low gradient and neuropathies including polyneuropathies and the autonomic uh neuropathies that we discussed. If at any point, your patient touches with the within those um those spectrums, they probably should be evaluated. And so how do we do that? So oftentimes it starts with history, we talk about things like heart failure symptoms, neuropathic symptoms. Uh you know, EKG findings could include low voltage, a pseudo infarction pattern. You know, lab results may show elevation of cardiac um biomarkers. Echocardiogram findings include LV, thickness, um loss of long strain, especially um with uh preserved apex, um low tissue uh velocities and per cardio fusions with a normal ef here's an example of one of my patients with, we see that there's a very slight pericardial fusion. Here's another example of that stream pattern and has that so called bulls eye or cherry on top pattern where the apex is preserved. And so at this point, you have enough information to decide, could this be amid doses or could it not be, could it be february HCM some other disease pathology? If it could be something else, then we do MRI. MRI. You may see things like subtle uh you know, like gaum enhancement consistent with amyloidosis, maybe subtle like this and maybe not so subtle like this. Uh And there are additional other findings including uh knowing the amount of cardi on I scout images and a few other elevated T one patterns, et cetera. If it couldn't be something else, then we should screen for a amyloidosis. And that includes getting uh serum uh free uh light chain assays and serum immun fixation. If those are positive if we see a monoclonal uh spike on the IFE if we see that the serum kapa lambda free light chain ratio is abnormal. Those patients should be immediately referred to hemant because it's an emergency that's negative. Then that takes us down the path of getting API P scan. Uh P IP scans is a bone and tigray scan. Um We should always order them with specked imaging because it improves the accuracy, the sensitivity and the specificity um because there are false positives with amyloidosis uh with a amyloidosis. Um But the skin itself uses a special kind of uh tracer tach Nesum and is taken up by the myocardium if they're amy fibros present. And so the scoring system we use is called the visual take score um to the left, we see a visual take score of zero, meaning no myocardium uptake to any of the techne. Then we see that the ribs in the serum are glowing bright white and that all goes all the way to a visual uptake score of three that we see on the right there where the myocardium is glowing bright, right bright white. And we see that there is no bone uptake at all and that would be markedly positive. Anything that's a two or a three, if there's myocardial uptake, that's significant equal to the bone or greater than the bone that's considered positive. So, if that's positive, we should get genetic testing, that's gonna help us determine if the patient has a hereditary variant or wild type variant, if that's negative, then you're kind of suckling back into the algorithm getting an MRI possibly a biopsy. So a few screening caveats, 30 to 40% of elderly patients with wild type att R have underlying MGUS. And if that's the case, we really need to have the hematology associates do a biopsy to confirm that it's not a Amy as well screen at center. So if you type in amyloid doses under the oro sets this pops up, you can choose between if it's inpatient testing or outpatient testing. Um the dropdown will have the same tests involved that includes the serum fixation and the uh light chain essays as well as the P IP scan with spec. And then once you obtain that by all means, feel free to loop us in and we'll be happy to help you interpret those results. I get a few questions about screening. Um It includes, you know, what do I do with light chain elevations without monoclonal spikes? Meaning they have elevated lambda, they have elevated Kappa, maybe the ratio is high but it doesn't meet the threshold. In that case, they may have an underlying MGUS. And oftentimes I encourage people to refer patients to hematology for evaluation. Another question I get is what do I do if the screen is negative? But I have a high clinical suspicion in those cases. If we're very concerned, we may talk about doing things like biopsies, fat pad biopsies, or even endomyocardial biopsies at the heart itself. Uh You know, more often than not, we'll have the patient, you know, have a screening protocol where maybe six months or a year later we'll repeat the testing. So a few cases that we talked about last time, um I introduced last time Mr C. Um uh Mr L and MT. Uh the interesting thing about this, this case series was actually this is a family. And so Mr C was homozygous for the mutation for V uh V 1 22 I, he had very significant disease and actually ended up needing a transplant. Uh Mr L was heterozygous. He actually had moderate disease and he did pretty well and I, you know, on uh you know, disease modifying therapies and he never, you know, needed to go on for advanced heart failure therapies. But MT was homozygous for mutation and she actually had no symptoms, no disease process and didn't require any treatment. And so this is actually a very interesting case series that really uh kind of shows that there's actually phenotypic variation both based on hereditary as well as sex. So oftentimes patients, male patients who are homozygous, they have very serious diseases. They oftentimes exhibit symptoms 10 years before the heterozygous counterparts. However, females, regardless of inheritance patterns, whether they're heterozygous or homozygous, whether they have one copy or two copies, they may never get any disease process itself. Um, you know, while, you know, for those patients, it's not as important as far as treatment goes. It may be important for family planning. Should they have sons? You know, there's a higher risk for that being passed on to their, their families. And so in regards to treatments, um, these patients are often intolerant of GDMT, um and diarrhea due to restrictive physiology and the fixed stroke volume, um rate control medicines, especially in a mid doses can cause brady cardia. And there's really, you know, limited evidence for the use of IC DS in this population. For a fib. These patients are often, you know, very intolerant of this. Uh they should be anti coagulated regardless of their SV score. Um And there's, it's really important that these patients should probably get tees every time we want to cardiovert them. Uh In one study, uh out of mayo, we found that there is a high incidence of left atrial pan thrombus. 33% of patients with amyloidosis had a left atrial pan thrombus, regardless of endo coagulation or onset of atrial fibrillation. Uh In addition, when you cardiovert these patients, there's actually a high risk of adverse effects. So there's a higher risk of VT VF bird is pacing of stroke and of just kind of transient shock at a 14% compared to their um nonn amyloid counterparts. And so that brings us to disease modifying treatments. So last year, I talked in depth in depth about the different trials and different medications. Um Here we see uh you know, the, the, the process of the liver making the TT R which breaks down into its uh monomers which then misfolds and then becomes aggregates that deposit within the myocardium, each uh variety of medication class acting in a different way. And so the first one that was developed are TT R stabilizers. TT R stabilizers. Uh They actually prevent the breakdown of that temer into the monomers. Uh that includes uh dilute and accor. So we see that stabilizer go and, and prevent that breakdown into the monomer. Um to feminist is really the main medication we use. The other uh name is Vida Max. It's an oral pill. Um It's fairly well tolerated. I have not really heard of many adverse effects. Uh In addition, that requires no additional testing. Uh you know, there's no concern for liver or kidney dysfunction. Um and this is really kind of what's considered probably the backbone of treatment of Amy doses at this time. Uh Difonzo is really only approved for people who can't tolerate other medications and a, you know, is still being studied, but it hasn't really uh you know, shown as much benefit. Uh So the next class of educations uh are TT R silencers and so TT R silencers, what they do is they actually uh limit the transcription and the production of TT R up to 85 to 90% total. And so if, if the of the stabilizers were the backbones of treatment, the this is gonna be the kind of the next frontier. So there's two categories, there are these antisense gluts that includes Eoin and plain. There are these um you know, uh uh silencing RN A molecules. And um and, you know, they actually work pretty, pretty darn well. And so the first one in was the first generation, it was originally subcutaneous injected. Uh Once we uh once per week, the next generation was a, they actually changed the, the log in to make it more specific. So there's less adverse effects and that's a sub in uh injection weekly as well. Um As far as the SI RNAs participant was the first generation of this that uh requires an IV infusion every three weeks. And the next generation was of a true and, and that's really the uh the next part of this uh of the SRN A SS A subcutaneous injection every three months. Um A lot of these, you know, the great thing about the, the um the silencers is, you know, the trials themselves, they're oftentimes broken down into uh primary neuropathic or primary cardiac patients. However, in the, the neuropathic side of, of these arms oftentimes they include patients with cardiac manifestations. So there's often times subgroups where we can see that there's benefit in both the neuropathic and the cardiac side of things. So the next uh And last category of treatment are these tt r disruptors. Uh that includes uh novel medications including doxycycline, used with bio acid derivatives. Um green tea extract at very high doses and monoclonal antibodies. And so these themselves, they, they, they are thought to kind of attack the fibro and break them down and prevent further uh aggregation accumulation and reduce the manifestations and the dysfunction of the heart. Um It was a medication as a mono clone, an anybody, it didn't really work out that well and it stopped being studied. Pr X 004 was a medication that was developed during, you know, right before COVID happened, the, the trial itself was put on hold. Um And so now that trial is underway and it's actually a monoclonal antibody that attacks the TT R crowd trip. So it's thought that it could break it down uh more to come in in the future with this. Um And while those were the traditional treatments I've actually had um and see more about this using CRISPR as a, as a, as a form of treatment. So actually modifying people's DNA uh going in snipping out that uh that mutation to, to reduce uh the TT R itself. Um It sounds pretty novel. I've actually had patients ask me about this, you know, can you refer me for CRISPR? Can I get this done? So, you know, more to come in the future with this. Of course, there are medical ethics to be concerned about. Um So in regards to treatment, you know, before 2018 we had zero modalities. In 2019, the feminists came around, we had one treatment modality and now we're looking at six or more. Um, so now we've talked about who do I test, um, who, um, how do I test and what medications should and shouldn't be used a few pearls uh would be to have a high level of clinical suspicion. Should a patient have LVH neuropathic symptoms and, or a stenosis screening is very important. Uh If you could start in your office or in, in the, in the uh the hospital, that'd be great more than happy to, to be uh available to help with that as well. Um Always order your P IP scans with spec um traditional volume management strategies and GD MP can be harmful in these patients. Be mindful of atrial fibrillation. There's high adverse effects of these, these patients with a fib and then there are treatment modalities that we can use to slow the progression of disease. Um and more on the horizon. But early referral is key. The earlier you refer them, the earlier you diagnose them, the better off they'll do long term. So next, we'll transition to cardio oncology. Um The importance uh behind cardio oncology. Uh you know, cancer patients are the fastest growing population at risk of cardiovascular disease. There are more than 15.5 million cancer survivors in the United States. Uh So the cornerstone to this is a multidisciplinary team, um you know, phase one really happens uh early on it happens uh in the the planning phases of the oncology treatment, you know, that includes really determining functional class. Are there any cardiovascular risk factors? Are there things we should be concerned about? Are there anything that we can mitigate, can we mitigate risk prior to starting chemotherapy? Because oftentimes chemotherapy can be hard on the body, including the heart. And so our goal is to make them as healthy as possible before they go into chemotherapy. Phase two occurs during chemotherapy. And that's, you know, establishing screening protocols, making sure that we keep patients as healthy as possible going through chemotherapy to keep them on chemotherapy to treat them and then phase three of survivorship. So it's gonna be early recognition of long term side effects, thinking about things like anthracyclines, it's gonna be treating patients with have SIA like radiation and chemotherapy related complications and then it's also developing kind of healthy uh learning patterns, et cetera. Uh Well, that looks like that concludes my uh my talk. Unfortunately, I have 15 minutes. But uh in the end, you know, I think the the point is that, you know, there are a lot of patients out there with amyloidosis that we could do a better job at screening. Um We're always here to help. Uh and then as far as cardio oncology goes, uh you know, these patients, um you know, they require a high level of care and uh uh follow up and we're more than happy to help and assist in any way possible. And so thank you. Uh thank you very much for everything. Published October 18, 2023 Created by Related Presenters Zackary Tushak, D.O. Sentara Advanced Heart Failure Center View full profile
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