In this episode of AP Cardiology, Andrew Perry, MD, interviews Frederick Ruberg, MD, of Boston University School of Medicine. They discuss heart failure with preserved ejection fraction (HFpEF) as a “diagnosis of exclusion” and give special attention to the topic of cardiac amyloidosis.
A transcript of the podcast follows.
Perry: Hey, everyone. Andrew here. I have another episode for you today that I recorded while attending the American Heart Association conference in Philadelphia in November of 2019. I attended a session on updates in heart failure with preserved ejection fraction and one of the speakers, Dr. Rick Ruberg from Boston University, gave a talk about excluding other causes when you’re making the diagnosis of HFpEF. In specific, we discuss more about cardiac amyloidosis.
First, we discuss what it means to actually carry the diagnosis of heart failure with preserved ejection fraction and then we go into discussing patients with cardiac amyloidosis and when to consider that diagnosis and specific populations in which that disease is more prevalent. If you look back at some of the previous episodes, you’ll find an episode published in December of 2018, where I spoke with Dr. Daniel Lenihan about cardiac amyloidosis. That episode and this episode both complement each other very nicely in referring to different trials and other populations. If you haven’t already listened to that episode, I would highly recommend going back and listening to that one as well.
Much thanks goes to the folks over at MedPage Today, who helped make these interviews while at AHA possible. Also, if you haven’t caught on by now, I’ve been recording heart sounds recently while on service with consults and on the wards with using the Thinklabs One digital stethoscope. The Thinklabs One digital stethoscope is a best-in-class sound quality and amplification stethoscope to help you hear hard-to-miss heart sounds. With that, we’ll get started with today’s episode.
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Perry: This is AP Cardiology and this is your host, Andrew Perry … Thank you for meeting with me today, Dr. Ruberg. Can I have you say your name and your title for our audience?
Ruberg: Sure. Thank you. It’s a delight to be here today. My name is Rick Ruberg — or Fredrick Ruberg is my given name — and I’m from Boston University School of Medicine in Boston, Boston Medical Center. I am the Associate Chief of Cardiovascular Medicine for Academic Programs and also I am the Associate Director of the Cardiology Fellowship Program. I have a sense of kind of a lot of different aspects of the academic job.
Perry: Perfect, thank you. We’re meeting today at American Heart Association conference in Philadelphia. You gave a talk this morning about heart failure with preserved ejection fraction (“It’s a diagnosis of exclusion, so exclude other causes!”). As going through internal medicine residency, I picked up a notice that the diagnosis of HFpEF, as we’ll abbreviate it, is used almost non-discriminantly and used a lot. I think before we talk more about excluding other causes, I kind of want to ask you about how do we define HFpEF, truly HFpEF?
Ruberg: That’s a very difficult question and many specialists struggle with that, so there’s no straightforward answer, but there’s a lot of different ways to think about what heart failure is. We’re talking about heart failure. That’s the HF part of it. I think with HFrEF, which the abbreviation for heart failure with reduced ejection fraction, it’s easy because we have some empiric measure that the heart function is abnormal, the ejection fraction. With HFpEF, the heart can look structurally normal echocardiographically. It becomes more challenging to really identify and merge the symptoms the patient is experiencing with a cardiac problem.
By definition, HFpEF really is the inability of the heart to adequately circulate volume at an acceptable pressure. That’s kind of how we describe what heart failure is and that happens when the ejection fraction is normal or the ejection fraction is not normal. HFpEF is when the EF is normal. There are so many aspects to that question. First of all, we don’t quite exactly know where that cut point truly is, and there’s some recent evidence that suggests that maybe we should be using a different cut point for what the EF is, defining HFpEF versus HFrEF.
Perry: Just to interrupt for a bit. We’ve previously been using 40% or greater as being HFpEF.
Ruberg: Right, exactly. Normal ejection fraction, depending upon which modality you use, is somewhere around 55% to 65%. Modality being whether you use MRI or echo or angiography or nuclide ventriculography and HFrEF is less than 40, but we have this defined intermediate area where the EF is not quite normal. It kind of speaks in some ways to the difficulty of using EF as our discriminating variable, but that’s another discussion. HFpEF basically is the concept that patients have symptoms of heart failure. Those include things like shortness of breath, elevated neck veins as an indicator of right-sided dysfunction. The shortness of breath would be indicative of elevated left atrial pressure, lower extremity edema, swelling because of high right atrial pressure, fatigue, problems with circulation, basic general weakness, exertional breathlessness. These are all symptoms of heart failure.
Perry: It’s a clinical syndrome.
Ruberg: It’s a clinical syndrome and it’s often associated with many other problems that either are coexistent or probably more likely contribute to the development of that syndrome. One can’t think about it just in isolation. It’s a very complicated problem. Again, HFrEF is, in some ways, a much easier problem to understand because the myocardial function is not normal. There’s a systolic problem and oftentimes the heart dilates and that leads to physiologic or non-physiologic remodeling that causes the increase in pressure.
With HFpEF, it’s different. I mean there could be a myocardial problem, like fibrosis or stiffening of the heart, but HFpEF also can be seen in situations where you have increased volume such as chronic kidney disease or chronic lung disease or obesity or metabolic disease like diabetes. Hypertension, obviously, is I guess the cardinal associated factor with HFpEF, but that’s also not exclusive either. It can be really confusing. I think when you’re approaching a patient you have to think about those symptoms, and then obviously — maybe not obviously — the first-line test that one gets maybe after one checks a BNP, NT-pro-BNP serologically would be an echocardiogram. That’s when we can make some estimates in the echocardiography laboratory of filling pressures and whether or not we think there is evidence of diastolic or systolic dysfunction, but it all is really a clinical integration, and one test doesn’t actually make the diagnosis.
Perry: Perfect. I love that. Just as a summary. Heart failure is a clinical syndrome. Then after establishing that syndrome, we then use an echocardiogram and BNPs to probably help confirm that. Echocardiogram to then stratify which type of heart failure we’re now dealing with.
Ruberg: That’s right.
Perry: Once we have then entered into that area of having HFpEF, there are numerous causes that can lead to a heart failure syndrome and then have an ejection fraction. What are some of those alternative diagnoses?
Ruberg: Most commonly, patients who have HFpEF will have the risk factors that we think about that are associated with the development of cardiovascular disease. Things like hypertension, obesity, diabetes, metabolic syndrome, and they often have comorbidities, say, chronic lung disease from cigarette smoking or chronic kidney disease from uncontrolled diabetes or hypertension. These comorbidities contribute to the development of HFpEF, but there are other diseases that I particularly am interested in that can also result in the clinical phenotype of HFpEF in the very simplistic sense that the ejection fraction is normal echocardiographically and they have heart failure.
Those diseases are, in some ways, kind of masked under the context of all these other common things. A lot of what I have been working on in my clinical and research work is to try to disentangle that signal of infiltrative heart disease or inflammatory heart disease less likely, but infiltrative heart disease that causes this phenotype of HFpEF. In specific, I’m talking about amyloid heart disease because that’s the disease I particularly study. Recent evidence has suggested that may constitute a sizable proportion of patients with HFpEF that have previously been unrecognized.
Perry: Gotcha. Yes, I think in your talk this morning you mentioned a paper from one of the European journals about how there’s possibly, amongst inpatients hospitalized with HFpEF, up to 10% to 15% prevalence of amyloidosis.
Ruberg: That’s right. There are certain populations of patients in whom we believe that one should look in a more targeted manner for amyloidosis, and the reason why it’s important is because amyloidosis, it’s different than the other processes that cause HFpEF. In this case, you have a clearer myocardial problem. Amyloidosis is a protein-folding problem where abnormally folded protein deposits in the heart, also other places in the body, too. There is a particular kind of amyloidosis that’s called ATTR amyloidosis. A for the amyloid. TTR because it’s the TTR or prealbumin protein that misfolds that causes the disease. That disease is seen really in older people only. When that happens, the heart becomes basically infiltrated by this abnormally-folded protein that leads to thickening of the heart muscle, impairment of relaxation of the heart muscle, and diastolic dysfunction, as well as some systolic dysfunction. But in the very early to middle stages of the disease, the global measure of heart function, i.e. ejection fraction, is normal. Therefore, these patients can have pretty profound abnormalities of heart function, but the EF is still normal. Again, speaking to the kind of challenge of using ejection fraction as our be-all-and-end-all parameter. It’s important because we now have treatments for this disease, and so making that recognition early is critically important.
Perry: Then when we start thinking about evaluating these patients in the inpatient or even the outpatient setting after having been hospitalized and thinking about whether they have amyloid, 10% to 15% is very high. But if we’re starting to think about a screening modality, the options that we’re left with, like cardiac MRI or these technetium-pyrophosphate scans, that could really rack up a large bill if we’re going to scan all of our patients with HFpEF to look for this 10% or 15%. I guess my question that I’m getting to is how do we increase the yield of our pretest probability and filter out that population even more? What are maybe some specific examples you could give us of where to think about that?
Ruberg: That’s an excellent question because these tests are not inexpensive, although pyrophosphate imaging isn’t that expensive compared to MRI. MRI tends to be more expensive depending upon where you live and who’s paying for it, but we haven’t gotten to the point and nor should we get to the point where we know what the right screening method is for older people. There’s many ways you can look at this. You could say, “We’re going to start with all people who have the phenotype of HFpEF. They already have heart failure, so we’re going to screen them.” Or you could say that all older people with other signals are things that we should think about screening. The reason I mention that, not to confuse the listeners, is once they develop heart failure, it’s not too late. We can certainly treat them and we know the drugs work. But if you think about primary prevention for coronary heart disease, we don’t start people on statins, for example, or treat their hypertension when they already have an MI. We do that, but the idea is you want to treat them before they have their MI and reduce the likelihood they’re going to develop it.
The same thing can be looked at, that sort of lens can also be looked at in amyloid heart disease. Sure, we should recognize people who already have HFpEF and screen them with pyrophosphate imaging or MRI, but we should also maybe think about looking a couple years forward, I guess, or before they actually develop HFpEF. We believe, the people who work on this, I think it’s a pretty shared consensus, that there are other manifestations of disease that may be orthopedic or other subtle manifestations, say, by echocardiography that can be identified before the onset of heart failure, because I think the gold standard is tissue biopsy, but you can’t just biopsy everybody’s heart. You can, but that would be a really poor screening strategy, both from expense and risk. But it is the gold standard. The idea is to identify non-invasive ways, whether they’re serologic, because there’s some potential serologic clues, looking at prealbumin concentration or retinol-binding protein 4, which is a molecule that we’ve been studying, or imaging to identify people earlier.
Other things that have been looked at are using iterative machine-learning algorithms to identify patterns and, say, the echocardiogram before someone develops amyloidosis. But I do think that a lot of our work is really focused on the phenotype that is already developed. We are moving the needle towards earlier disease identification.
How do we do it? There are certain populations of people that we believe are disproportionately affected by amyloidosis. They’re all older. Because the disease, interestingly even though we all make the molecule prealbumin, some of us will develop ATTR amyloidosis and without any genetic mutation. Others of us will inherit a mutation, the TTR protein, that will lead to the development of the TTR amyloidosis phenotype. But it’s always over the age of 40, at least, for certain hereditary forms and really over the age of 60 for the most common type of amyloidosis that’s called ATTR-wildtype where the genetics are normal.
Perry: This probably needs to be further understood. There’s probably not a great understanding of that pathogenesis that takes decades and years.
Ruberg: That’s correct. Something happens, whether they’re epigenetic factors, whether they’re environmental factors, whether it has to do with the inability of the liver tissues, for example, to manage misfolded TTR protein. This is interesting when you think about it in the context of other protein-folding diseases such as brain Alzheimer’s disease. CNS disease, Alzheimer’s disease, is obviously a protein-folding problem as well. There’s no known association with systemic amyloidosis that we know of at the present time in that there’s not a genetic factor that leads to one or the other. But for reasons that are not entirely understood, TTR protein and amyloid beta misfold. In the brain, it’s more complicated because I think it’s not entirely clear whether or not the protein is actually the cause of or just a marker of other disease. Whereas in systemic amyloidosis, the protein clearly is the cause of the disease. But that being said, the accumulation of protein is not known.
Then, we think about with these populations. The specific populations to think about are older people, any older person with heart failure, first of all. I think it should be on differential diagnosis. But generally speaking, someone with heart failure and normal wall thickness and a low ejection fraction is not likely a patient with amyloidosis. Whereas an older person with thicker walls, say over 12 millimeters by echocardiography — and again, that’s also an imperfect parameter, over 14 millimeters with heart failure — with a preserved ejection fraction or not because later in the disease the ejection fraction falls. That’s another group of people.
There’s a particular mutation. Mutation isn’t a very nice word. It’s really a polymorphism. But the genetic term is mutation, where basically there’s a single nucleotide change in the TTR protein. It’s called V122I, and it occurs in about 3.4% of U.S. African Americans, which translates to 1.5 million people carrying this allele V122I, which incidentally is read out by 23andMe, for example, so people could know their own genotype in that respect.
We really don’t understand what the genetic penetrance of ATTR amyloidosis is, meaning how many people who actually acquire the gene will ultimately develop amyloidosis? When they develop it, we also don’t know. It depends. If you look at a 45-year-old who has V122I, they’re very unlikely to have amyloidosis. But an 85-year-old? We don’t know and that’s a study that we’re actually doing right now in Boston and New York. Other disease, other populations, subpopulations, the aortic stenosis patients with low-flow, low-gradient phenotype. That’s been shown.
Perry: I was particularly interested about that because there was a fairly high prevalence, I think, that you reported in this morning’s talk, like 30%?
Ruberg: Right, so 30% of the patients with low-flow, low-gradient aortic stenosis in a study of TAVR patients, transcutaneous AVR patients, about 150 patients from one center, Columbia. About 30% of them had unappreciated cardiac amyloidosis. Of all the people undergoing TAVR, so for severe AS, exactly 18% and 22% of men, most of them were men, had cardiac amyloidosis.
Perry: I think that’d be a particularly hard population to identify. Because with their aortic stenosis, they’re going to develop a lot of left ventricular hypertrophy anyway.
Ruberg: That’s right.
Perry: Then, I don’t know.
Ruberg: It’s hard. The other question is what do you do about that? Do you go ahead and do the TAVR? Do you put them on drug therapy to slow their amyloidosis? There’s a drug available now called tafamidis, which has been approved. I’ve seen a number of these patients now in referral and what I’m recommending is that, especially if they’re more… and it’s also impossible, I should back up. How do you know the severity of the disease? We have ways to assess amyloidosis severity echocardiographically and by biomarkers, but the AS messes that all up, so you don’t really know whether their echo looks the way it looks or their biomarkers look the way they look because of their AS or not.
Generally speaking, I recommend, if possible — and that’s a lot of considerations here: age and the severity of the heart disease, comorbidities, coronary disease, etc. — fixing the aortic stenosis, because even palliatively, that generally makes people feel better. Then consider treating them for ATTR amyloidosis with tafamidis or diflunisal, which is another potential agent that could be given in certain patients. But it becomes confusing and there are issues of cost and all that because TAVR is not inexpensive and the treatments for amyloidosis are expensive.
Perry: I think you’d also mentioned patients with hypertrophic cardiomyopathy, that there can be some overlap there as well.
Ruberg: Right, because hypertrophic cardiomyopathy can look very similar to amyloidosis. I’m not talking about the 20-year-olds or the 18-year-olds or the 22-year-olds who have hypertrophic cardiomyopathy. Those patients don’t get amyloidosis. I will be completely transparent. There are some very, very uncommon mutations that can occur very early in people in their 20s, but those are almost never seen and most practitioners will never encounter them. Most commonly, someone who is 20 years with a wall thickness of 16 or 18 or 20 millimeters does not have amyloid heart disease. They may have HCM, hypertrophic cardiomyopathy, or a phenocopy of HCM, a storage disease which also can look like HCM. But we believe — and again, we being people who work in this area as a handful of centers that are exploring this — that patients who are older who are diagnosed with HCM for the first time, a sizable portion of them probably have cardiac amyloidosis as the cause of their wall thickness and that’s just an education thing, I think. It’s just people don’t think about it. I suspect it’s probably more likely that if they’re older, say over the age of 70, develop wall thickening, they’re more likely to have cardiac amyloidosis than to have HCM.
Perry: Gotcha. To kind of summarize, our patients who maybe have a higher pretest probability and we’re talking about orthopedic manifestations, I was assuming that meant carpal tunnel syndrome.
Ruberg: That’s right.
Perry: In particular bilateral carpal tunnel syndrome.
Ruberg: Precisely.
Perry: We’re talking about patients with a specific phenotype of low-flow, low-gradient aortic stenosis. There are African Americans who carry this polymorphism that has them at increased risk. Then older patients who present with hypertrophic cardiomyopathy or at least that phenotype may have amyloidosis as well.
Ruberg: That’s right. There’s some clinical clues whether amyloidosis is there or not, and I can provide some for your listeners. Again, these are not absolutes. I think you win if you just think about it. You’re already ahead of the game if it’s on your differential diagnosis and you know how to apply the testing to figure it out. How do you know how to do that? We now finally have guidelines and consensus statements that actually help guide and unify the acquisition and interpretation of imaging data. Again, because I said you’re not going to biopsy everybody. That’s impractical. We agree on that.
There’s a publication. It’s actually a two-part publication that was published earlier this year in the Journal of Nuclear Cardiology and also in the Journal of Cardiac Failure. Both of these two are co-published, so I would urge the listeners to look at that to understand. It’s very well done and it really kind of looks at each modality and how to interpret the testing. Anyway, once you’ve figured out, I think that, as I said, you think about it first and then you apply the appropriate testing. But some clinical clues would include — for example, and this requires integration of clinical phenotype and testing — anybody who, for example, we talked about the orthopedic manifestations. Anybody who has bilateral carpal tunnel syndrome and, say, lumbar spinal stenosis or a tendon rupture, because amyloidosis deposits everywhere in the body and we understand that there are some proportion of people who develop thickening of the ligamentum flavum, of the spinal column, that leads to spinal stenosis. We don’t know the proportion exactly.
People who develop spontaneous tendon rupture of, say, the biceps tendon. That should be a clinical clue. Again, these things happen. A lot of people get spinal stenosis and a lot of people get CTS and a lot of people have tendon rupture. Which of those have amyloidosis? That would require further imaging, but it should be on the differential. Anybody who cannot tolerate beta blockade. A new heart failure patient, guideline-directed therapy would suggest that you want to put them on a beta blocker, but then they develop hypotension and profound fatigue and feel awful on their beta blocker. That’s unusual. That suggests that they may have restrictive cardiomyopathy that you didn’t appreciate, and they really are dependent upon that contractility and also dependent upon that heart rate for cardiac output.
By that token, anybody who used to have hypertension and all of a sudden you peeled away their blood pressure medications and their wall thickness is increasing or it’s just abnormal. That’s weird. Again, that certainly happens with age. People often require less because there’s the capacity, the systems change, and the blood vessels change in terms of their stiffness and all that. But again, it should be on the differential diagnosis, especially in the context of a thickening heart.
Anybody who, say for example, has increased echocardiographic wall thickness, but ECG looks like they’ve got low voltage, that’s weird. Most people who have hypertensive heart disease and hypertrophic cardiomyopathy have thick walls, but they also have big volts on their ECG. Again, there’s many other reasons why someone might have low voltage on their ECG pattern, but that conjunction of those two observations should trigger a thought process that maybe this patient might have amyloidosis. Again, in a 25-year-old, I wouldn’t think about it, but in a 75-year-old? It would make me pause.
Perry: Gotcha. I really appreciate you visiting with me and talking about those. I could probably ask you a whole bunch of other questions and go on more and more, but I appreciate that.
Ruberg: I’m glad to share and I hope it was useful to you and your listeners. If anybody has questions about what I talked about, they’re welcome to reach out to me or there are a lot of resources out there where you can ask an amyloid specialist if you have specific questions. But our mission, those of us, again, who work in the areas I’ve alluded to, this nebulous “us,” is really to kind of increase awareness and get people, especially trainees, to think about it because this is not a rare disease anymore, and it’s something that you will definitely encounter in your clinical practice.
Perry: Actually, now that you mention that about ways to reach out. Are you on social media?
Ruberg: I should be on social media. I’m totally dating myself. I should be on social media. There are many reasons why I’m not, but no, a standard email would be completely fine. My email is just my first name, fredrick.ruberg. My last name @bmc.org. Also, there are many, as I said, there’s many websites. Amyloidosis Foundation, Amyloidosis Research Consortium, and amyloidosis support groups are all conduits, basically, that patients and providers can use to find more information.
Perry: Great! I’ll find those consensus statements and put those in the show notes.
Ruberg: Sounds great.
Perry: Thank you, again.
Ruberg: My pleasure.
Andrew Perry, MD, is a cardiology fellow at the University of Washington Medical Center in Seattle.
Source: MedicalNewsToday.com
