Cardiac Amyloidosis: The Great Imitator

Martha Grogan, MD; Angela Dispenzieri, MD; Nandan S. Anavekar, MB, BCh


September 08, 2014

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An Elusive Diagnosis?

Martha Grogan, MD: Hello. I'm Dr Martha Grogan, a cardiologist and director of the Cardiac Amyloid Clinic at Mayo Clinic in Rochester, MN. Today we have convened a roundtable review on cardiac amyloidosis. It's my honor to discuss this topic with Dr Angela Dispenzieri, professor of medicine and laboratory medicine and a consultant in hematology, as well as a world-renowned expert in amyloidosis; and Dr Nandan Anavekar, assistant professor of medicine, a senior associate consultant in cardiology, and an expert in cardiac imaging.

The goal of our discussion today is to discuss the fascinating disease of cardiac amyloidosis, to raise awareness in the cardiology community, and to review the crucial steps in establishing the diagnosis and the treatment plan.

I find it very interesting that patients are understandably frustrated with how long it can take to establish a diagnosis. We see this not only when patients are referred to us, but Angela and I participate in the support groups, and patients often spend two to four years seeing many cardiologists before receiving a diagnosis.

Patients can present with heart failure, chest pain, arrhythmias, atrial fibrillation, orthostatic hypotension, or unexplained stroke caused by cardioembolism. There are many different manifestations.

What are some of the other factors that should make a cardiologist suspect cardiac amyloidosis?

Angela Dispenzieri, MD: Amyloid is a great imitator, and many other symptoms can go along with it. Nephrotic syndrome, possibly with edema or an unexpected rise in lipid levels (which would go with nephrotic syndrome) is sometimes a clue. Another is signs of neuropathy—carpal-tunnel syndrome, a small fiber neuropathy, or a painful neuropathy—and hepatomegaly. The textbooks show other signs, such as periorbital purpura.

Dr Grogan: How often does that happen?

Dr Dispenzieri: It's very rare. Therefore, one should not rely on finding these rare symptoms to make the diagnosis of amyloidosis. One has to have a high index of suspicion when patients present with the other less pathognomic presentations—cardiomyopathy, nephrotic syndrome, and peripheral neuropathy.

Different Types, Different Diseases

Dr Grogan: There are different types of amyloid, which can make it confusing for cardiologists. I was happy to hear that the hematologists even get confused if they are not experts in dysproteinemia. For cardiologists, there are only three main types, although many different proteins can make amyloid.

Most cardiologists know the amyloid light (AL) or light chain type from their training or textbooks. With respect to the transthyretin (TTR) type, there is a rare form—the hereditary type—that is not rare in blacks. As many as 3% to 4% of the population are carriers. The type that historically we called "senile" is now more appropriately called wild-type TTR or age-related TTR.

Those are the three types that cardiologists need to know about. It's important to realize that they are very different diseases. They present differently. As we start thinking about diagnosis, what tools do we use to try to work up a patient with suspected cardiac amyloidosis?

Dr Dispenzieri: Many cardiologists are keyed in to the AL type, so they tend to order the serum protein electrophoresis, looking for a monoclonal protein or a monoclonal spike. Unfortunately, that test will miss it more often than it finds it, because it is not a very sensitive test. The idea is good, but it's only halfway there. They also need to do an immunofixation test. There is another test called the serum immunoglobulin free light chain, which measures the immunoglobulin light chains that are the building blocks for amyloid.

Using the serum protein electrophoresis with immunofixation and the serum free light chain will capture about 97% of AL cases, but not TTR, because they are not related to the immunoglobulin. A 24-hour urine protein electrophoresis with immunofixation will find up to 99% of AL cases.

Dr Grogan: If we do the immunofixation, and the serum free light chains, the urine test, and a fat pad aspiration, we will identify most patients.

Dr Dispenzieri: Right. The first question is whether there is a clonal disorder. The second is whether the patient has amyloidosis. I have a suspicion that the patient might have amyloidosis, but is it correct? It is a tissue diagnosis, so one of the easiest tests to do is to do what we call a fat pad aspiration, or some do a fat biopsy. If you see the amyloid there, then you can say, "We have the monoclonal protein." Ideally, you want to type the amyloid. In cardiology, there are three major types of amyloid, but there are actually more than 25 proteins that can cause amyloid disease. You need to make sure that you know whether the amyloid is AL or TTR, because the implications in terms of prognosis and therapy will vary accordingly.

Dr Grogan: We have seen, as have the hematologists, that cardiologists are diagnosing amyloidosis more because of the availability of cardiac MRI, a tool that has helped us a lot. Echocardiography should not be underestimated. It is a fantastic screening tool and often is the first test to suggest the diagnosis, although in some patients, amyloidosis is not obvious on echocardiogram.

Cardiac Imaging in Amyloidosis

Dr Grogan: Nandan, you are an expert in cardiac MRI. If I am the referring cardiologist, what do I need to know about the MRI, and should I screen my patients for amyloid using that test?

Nandan S Anavekar, MB, BCh: Imaging is fundamental to understanding whether there is cardiac involvement, and echocardiography has been the mainstay. Cardiac MRI is evolving as one of the main players in understanding cardiac involvement with amyloidosis.

With cardiac MRI, a few clinical issues need to be understood. To study the presence of amyloid in the heart using cardiac MRI, the patient has to receive contrast, and the contrast agent is a heavy element called gadolinium. The most important factor that precludes the use of gadolinium is renal disease. Unfortunately, as recently as 1997, there were reports of nephrogenic systemic fibrosis, a devastating illness that was causally related to gadolinium administration in renal disease.

Other important issues don't necessarily come to surface. For example, the MRI scanner is a very tight space, and some patients have claustrophobia. The duration of a cardiac MRI is up to an hour, a long time for some patients to remain in the scanner lying flat, particularly those with congestive heart failure

To do the exam properly, we need to communicate with the patient and have the patient's cooperation with breath holding throughout the scan. If the patient has back problems or heart failure (which many of these patients do), it can be very tiring for the patient. All of these issues must be understood before proceeding with the MRI.

Dr Grogan: What are the technical factors that the imager needs to know to make sure that a proper examination is obtained?

Cardiac MRI Interpretation

Dr Anavekar: Two parts of the cardiac MRI examination are important when assessing for cardiac amyloidosis. The first is to look at the cardiac morphology (structure and function). The workhorse sequence that we use is called "steady-state-free precession." With that pulse sequence, we are able to look at left ventricular and right ventricular chamber size. We are able to look at atrial-wall thickness. We are also able to look at pleural and pericardial effusions, which can be important in the presentation of these patients, and we can look at the volumetric assessment of cardiac function.

The integral part of the examination is known as "tissue characterization." It requires that we inject gadolinium, and a normal kinetic profile in seen in normal people, but dyskinetic areas are abnormal in the setting of amyloidosis. Cardiologists will hear the term "abnormal delayed enhancement," which is sine qua non of what we find on imaging in these patients.

The hyperenhancement can be variable. Typically, it is subendocardial or entirely diffuse. The other very important aspect of the gadolinium contrast agent is that it can also be used with delayed imaging to look for intra-atrial thrombi, another complication of the disease.

The key question is how can we determine the presence of cardiac amyloidosis vs the abnormal delayed enhancement that we see in other nonischemic cardiomyopathies, especially those that are associated with increased wall thickness such as hypertrophic cardiomyopathy? And the key point here—it can be a little bit confusing, but it's a technical aspect, and it's referred to as abnormal myocardial nulling.

During the examination we use a pulse sequence that suppresses a signal from the desired tissue so it enhances the pathology. For example, if you are looking for a myocardial infarction, the normal myocardium will be dark, but the abnormal myocardium will brighten up, suggesting an infarction.

A pattern of myocardial nulling is related to the blood pool nulling. The key in amyloidosis is that this pattern is reversed, and it can be graphically represented with the software that is used to study patients. That is the key point of our examination.

Dr Grogan: Can the abnormal nulling be missed, depending on the timing of the sequences? How does the referring cardiologist know whether the nulling sequence was done properly?

Dr Anavekar: If we see that abnormality, we are confident of an infiltrative cardiomyopathy. The absence of that abnormality doesn't exclude the diagnosis, which is based on the integration of the clinical, laboratory, and imaging findings.

Dr Grogan: There are different patterns of amyloid involvement in the heart. We have seen some unusual MRIs because it was mostly endocardial. And the imager might not recognize that it's amyloid. We have to be aware that with a rare disease, there are variations on imaging. However, if I see that the nulling is abnormal, I am very suspicious. An abnormal pattern or delayed enhancement could represent other cardiomyopathies.

Dr Anavekar: The key is always pick up the phone. I tell my cardiology and hematology colleagues that if anything is unclear, give us a call and then we can go through the images together.

Other Diagnostic Tests

Dr Grogan: Sometimes we forget about such old-fashioned tests as electrocardiograms. The electrocardiogram is abnormal in the vast majority of patients with any type of amyloid, but it is very common in AL to see low voltage. This occurred in about 45% of patients in a series that we studied.[1] Typically about 50% have low voltage or a pseudo infarct pattern in which Q waves are present, but no regional wall-motion abnormalities on echocardiography. We have an increased index of suspicion when we see thick walls, low voltage, and pseudo infarcts, but normal voltage doesn't exclude the diagnosis. Many cardiologists think, "I looked at the EKG, and the voltage was normal." We have even had patients (about 16% in one of our AL series) who met criteria for left ventricular hypertrophy.[2] In the TTR type of amyloid, low voltage is less common, probably occurring in only about one-fourth.

The other issue is when to do an endomyocardial biopsy. Angela has mentioned that other organs can be involved. Typically for AL, we do a fat aspiration, a bone-marrow biopsy, and perhaps a kidney biopsy. If all else fails and we still have a high index of suspicion, we will do an endomyocardial biopsy. With suspected TTR, the need for an endomyocardial biopsy is more likely. If the cardiologist has a high level of suspicion, that biopsy must be considered.

Angela, can you tell us about the treatment options for patients who have AL amyloid with significant cardiac involvement?

Treatment for Cardiac Amyloidosis

Dr Dispenzieri: A huge spectrum of therapy is available compared with what was available before.

Dr Grogan: That's exciting. Just yesterday I heard a cardiologist say that he hadn't referred a patient because he thought there was no treatment.

Dr Dispenzieri: For AL, the treatment parallels that of multiple myeloma—we are receiving "hand-me-downs." Pills include such older drugs as melphalan and dexamethasone, and such newer medicines lenalidomide [Revlimid, Celgene], pomalidomide [Pomalyst, Celgene], and bortezomib [Velcade, Millennium Pharmaceuticals] (an injectable drug). These medications have been shown to treat the underlying bone-marrow process, which in turn allows the heart to improve.

We also provide high-dose chemotherapy with autologous peripheral blood stem-cell transplant. We used to call that bone-marrow transplant, but now we have a fancier expression for it.

Dr Grogan: If you mention stem-cell transplant, some people think it is cardiac stem cells. It is autologous peripheral blood—taking a person's stem cells and putting them back in.

Dr Dispenzieri: Yes, after high-dose chemotherapy. For the cardiac patients, there is a huge spectrum of severity. There are patients who say, "I used to be a marathon runner and now my mileage is down." Something is not quite right, but they still have an excellent performance status, so that is very early cardiac involvement. Other patients arrive in a wheelchair and oxygen because they are so far advanced. If cardiac involvement is mild, we consider high-dose chemotherapy with peripheral blood stem-cell transplant as an option.

In the more advanced patients, studies show that you would do them a disservice by trying to give such intensive therapy. In these patients, the lower dose or easier therapies give results that are just as good, if not better.

No Standard Heart-Failure Treatment

Dr Grogan: Some cardiologists think that the patient has to have stem-cell therapy, but that is not necessarily true. It's important for cardiologists to recognize that most of these patients, especially with the AL type of amyloid who present with heart failure, do not typically do well with beta-blockers and angiotensin-converting enzyme inhibitors—standard treatment for heart failure. Most of them initially have a preserved ejection fraction, although they can have low ejection fraction. Cardiologists are frustrated because they want to do something, but these patients have very severe restrictive hemodynamics with a fixed stroke volume and do not do well when you lower their heart rate or blood pressure, because many of them have autonomic insufficiency.

It's different with TTR, but most cardiologists should get the message: don't try to use standard heart-failure treatment. The hematologists stop it. The dysproteinemia experts take patients off of carvedilol and other medications.

How about digoxin? When we were residents, we were taught to never ever use digoxin. Do you ever use it?

Dr Dispenzieri: Yes, definitely I use it for rate control. These patients may have atrial fibrillation, and if the beta-blocker is going to decompensate them, you need to prescribe amiodarone or digoxin. The negative digoxin data are really an in vitro finding,[3] and patients with amyloid are known to have sudden death.

The digoxin isn't necessarily associated with sudden death.

Dr Grogan: In many patients we have to choose the lesser of the evils.

I often use digoxin for rate control of atrial arrhythmias. It tends to not lower blood pressure. But I watch the levels very closely, because the evidence against it is very weak, but it's on all the exams. Sometimes other providers stop digoxin that we just started, and that is frustrating. There should be an expert involved if you are prescribing digoxin.

Dr Dispenzieri: The other thing is that some of our drugs lower potassium levels, so you need to monitor that.

Monitoring Biomarkers

Dr Grogan: Cardiologists don't check troponin levels much in outpatients. What is the prognosis for patients with AL? Has it improved over the years?

Dr Dispenzieri: With Allen Jaffe and colleagues, we have started looking at using troponin and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) as major prognostic markers for patients with amyloid.[4] There have been iterative staging systems to use, but the most recognized are the thresholds of troponin T and NT-proBNP. You can divide patients into thirds and have excellent separation of curves in terms of survival. More recently, we have added the serum immunoglobulin free light chain to improve the staging and the separation of curves and predicting patient outcomes.

We use the cardiac biomarkers as exclusionary criteria for transplant. For high-dose chemotherapy and peripheral blood stem-cell transplant, we use thresholds based on our experience. We know that we can get a patient through a transplant if troponin T level is <0.06 ng/mL; treatment-related mortality is about 5%. If the troponin level is higher, mortality is 27%, so these levels do help us significantly.

From the NT-proBNP work out of Italy, in collaboration across the world, we have been using it as a response criterion to know how our patients are doing with chemotherapy. This is not new to cardiologists who follow heart failure, but we use it to very much gauge how our patients are doing and whether we think the chemotherapy is working.

Dr Grogan: It is important because often the imaging doesn't help much in terms of gauging treatment response. The wall thickening, by either echocardiography or MRI, doesn't help. Can the walls ever be normal in cardiac amyloid?

Dr Anavekar: Yes, that's a good point. Ideally, we want the textbook case on MRI with thick walls, but in reality the walls can be normal or subtly increased in thickness. It can be very difficult to use MRI as a diagnostic tool.

Dr Grogan: The nulling would probably be abnormal. We have had patients with relatively normal wall thickness but we picked them up with the nulling.

Dr Anavekar: Exactly. We need get a good look at the right ventricle, which may not be optimal using echocardiography. We can look at subtle increases in right ventricle wall thickness.

Dr Grogan: So MRI, especially in unexplained heart failure in general (but not particularly for amyloidosis), can be really helpful.

Dr Grogan: We talked about the rarer forms of hereditary amyloid, and there are many different hereditary forms, but cardiologists mainly need to worry about the TTR type, which can be either neuropathy or cardiomyopathy or an overlap of the two. In general, they are rare, except in those of Afro-Caribbean descent, as much as 4% of the population. If you see a black patient with heart failure, many of them will have a history of hypertension, but you can't just write it off as hypertensive heart disease. Those patients tend to have thick walls, and they often will have reduced ejection fractions.

Patients with the wild type or age-related type (most cardiologists still think of that as senile) often have very thick walls, but a much more indolent clinical course, and that is why those with AL might have normal wall thickness. It's because of toxicity of the circulating light chains and other factors that affect the myocardium directly, not just the amyloid infiltration. We just need to be aware, as cardiologists, that there are many different manifestations of this disease.

New Treatments for TTR

Dr Grogan: There is some very exciting work finally in the TTR type of amyloid, especially the seniles. We are seeing patients (the wild types) who in retrospect have had symptoms since their late fifties. These are usually men, not exclusively, but most are men, and it is important to diagnose these people earlier. Many times they present with arrhythmias, but they are not just 90-year-old people. What is the exciting news in TTR?

Dr Dispenzieri: There used to be nothing. It was an academic exercise. Now there are several drugs. One is called tafamidis [Vyndaqel, Pfizer] which stabilizes the TTR tetramer so that the little monomers aren't breaking off and forming fibrils. That drug has orphan drug approval in Europe. It has not yet been approved in this country, but there are going to be successor trials. There are also a couple of different molecules out there. One is ISIS-TTRRx (Isis/ GlaxoSmithKline) and the other is ALN-TTRSC (Alnylam), which actually reduces the amount of transthyretin that is being produced. The Alnylam agent was in the New England Journal of Medicine recently,[5] not yet about the effect that it has on the heart, but that it can silence RNA and knock down the levels of transthyretin. If you don't make TTR, you are not going to make TTR amyloid. That is pretty exciting. It adds to our armamentarium. Historically, we would occasionally do liver transplants for the hereditary amyloidoses to pull out the manufacturing plant of the abnormal TTR and put in a new liver. In theory, the patient shouldn't get worse, but transplant hasn't worked as well as we would have hoped, and for the age-related or wild type it's not an option.

Dr Grogan: Just to clarify, in the wild type, the molecular structure of the TTR is normal, but for reasons that we don't understand, it becomes misfolded and forms amyloid fibrils, so a liver transplant won't work for that.

The question of cardiac transplant also comes up. In AL, that is very controversial. You have to make sure that there is no amyloid elsewhere, but there is always going to be some. There are issues with these patients having the plasma cell clone under control.

The TTR amyloids, especially the wild-type patients—or even the familial type patients, if they don't have a lot of neuropathy—are often otherwise very healthy patients, but in the past, we diagnosed them when they were 85 years old. Recently, we have had patients who have been transplanted when they were identified early enough. But cardiologists also get confused because they think, amyloid, no transplant. That is not really the case in the age-related amyloid.

So thanks so much for your insight. It was great to have both of you join us today.

In conclusion, we have several important myths to dispel about cardiac amyloidosis. First, the absence of low voltage does not exclude cardiac amyloid. Second, a serum protein electrophoresis is not a good screening test for AL amyloid. MRI is a fantastic screening tool, but if the index of suspicion is high, one needs to consider a cardiac biopsy.

Treatment exists for all types of amyloid. This is not just an academic diagnosis. You will find that if you start looking for cardiac amyloidosis, you will find it.

Thank you all for your interesting insights on this topic and thanks to our viewers for joining us. We hope that you'll continue to follow us on our roundtable review series on


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