Hello, my name is Amrath Amberdecker. I am the Medical Director of Cardiac Transplantation at the University of Colorado. And in this session, we will be reviewing red flags and clinical clues, when to suspect cardiac amyloidosis. I would like to start with the case. A 75-year-old man presents to your office after a recent emergency room visit for palpitations and edema. He was found to have atrial fibrillation with a ventricular rate of 100 beats per minute. His echocardiogram revealed severe concentric left ventricular hypertrophy with a wall thickness of 1.8 centimeters, a normal left ventricular ejection fraction, grade 3 diastolic dysfunction, and severe biatrial enlargement. He was prescribed metoprolol, 25 milligrams twice a day, furosemide, 20 milligrams daily, and started on anticoagulation. You are seeing him in your outpatient cardiology clinic for follow-up. And on presentation, the patient feels very dizzy, but his edema is better. His ECG reveals atrial fibrillation with a ventricular rate of 50 beats per minute. And his ECG reveals normal voltage. His past medical history is notable for chronic back pain and spinal stenosis. He reports having regular medical checkups his entire life. He says that his blood pressure used to run 120 over 80, but since his emergency room visit, his blood pressure has been running 90 over 60. He has had labs in the last year as part of his primary care physician's annual follow-up. And it is notable that he has a normal SPEP. So the question to the audience, is an evaluation for cardiac amyloidosis indicated? A, yes, there are red flags for cardiac amyloidosis based on this clinical scenario. B, no, a normal SPEP excludes cardiac amyloidosis. C, no, the normal ECG voltage excludes cardiac amyloidosis. Or D, no, atrial fibrillation is never seen in cardiac amyloidosis. This is hypertensive heart disease. Cardiac amyloidosis is a rare disease. So obviously the answer to this question is yes, there are red flags for cardiac amyloidosis based on the clinical scenario. You probably were able to surmise that from the title of the discussion. But let's dive a little bit deeper into why an evaluation for cardiac amyloidosis is indicated and what are the clinical clues or red flags that should raise your suspicion to start to evaluate somebody for amyloidosis. So an important take-home point is that I want to dispel the myth. There is a myth out there that cardiac amyloidosis is a rare disease or a so-called medical zebra. And that is simply not the case. Amyloid is not rare. It is not a zebra. But you have to think about it if you are going to make a diagnosis. They sometimes ask the audience, do you have a patient in your practice with cardiac amyloidosis? And oftentimes people do not realize that they probably do. They just are undiagnosed. So among a survey of patients with a known diagnosis of amyloid transcyretin cardiomyopathy or ATTR-CM, 17% had visited five or more physicians before making the correct diagnosis. Greater than 50% of hereditary ATTR-CM and 39% of wild-type ATTR cardiomyopathy patients were misdiagnosed with an alternate condition. 75% of those patients were receiving treatment for a misdiagnosed condition. And hypertensive heart disease was the most common misdiagnosis. So if I ask that question again, do you have a patient with cardiac amyloidosis in your practice? If you answer you have a patient with HF-PEF or heart failure with preserved ejection fraction, statistically there's a good chance that there is a proportion of those HF-PEF patients in your practice that do in fact have cardiac amyloidosis. This is a study where the investigators looked at autopsy and looked for evidence of pathologic deposition of amyloid on autopsy samples from patients that had a diagnosis of HF-PEF. And if you look at the different age cohorts, there is a clear increase in the percent of wild-type TTR amyloid as patients with HF-PEF get older. The exact clinical significance of the amyloid deposition in some of these patients is uncertain, but it does stand to reason that there are a proportion of HF-PEF patients, particularly older HF-PEF patients that do have TTR amyloid that may be contributing to their underlying HF-PEF disease state. So cardiac amyloidosis is not a rare disorder, but it is a disorder where most patients do not have a formal diagnosis. If you look at the iceberg analogy, the number of patients that have a formal diagnosis is akin to the portion of the iceberg that you see above the water. By contrast, there is a large number of patients with undiagnosed or underdiagnosed ATTR cardiomyopathy that are below the water, so to speak. So among patients with HF-PEF, wild-type ATTR cardiomyopathy may be present in 12% to 20% of those patients. Similarly, among patients with low flow, low gradient degenerative aortic stenosis, up to 12% of those patients may, in fact, have ATTR cardiomyopathy. Let's go back to the case and review it again to see what are the clues that actually should have prompted us, in hindsight, to have thought about amyloidosis. So 75-year-old, that is the right age demographic. This is a patient with atrial fibrillation with a ventricular rate of 100 beats per minute, so perhaps slightly slower than you would expect. The echocardiogram shows severe concentric left ventricular hypertrophy with grade three diastolic dysfunction and biatrial enlargement, so there is evidence of perhaps something abnormal on the echocardiogram. If we go further, the patient feels very dizzy, and the ECG reveals a ventricular rate of 50 beats per minute. So this happened after starting relatively low doses of metoprolol. The past medical history is notable for chronic back pain and spinal stenosis. That should perhaps be a tip-off that maybe there's something more systemic going on. This is the patient with regular medical checkups, blood pressure 120 over 80, sounds like it is very well controlled. And then with the addition of a low dose of metoprolol, the blood pressure starts to get very low. That's another perhaps tip-off that perhaps there is something going on. So I do think in a scenario such as the case that I presented, it's important to think about what is the differential diagnosis for LVH. And actually, before we get too far ahead of ourselves, it is worth defining what is LVH. So LVH is left ventricular hypertrophy, and we are very quick when we read echocardiogram reports to say left ventricular wall thickening is left ventricular hypertrophy, but that may not actually be the case. So LVH is the result of myocyte hypertrophy. And in conditions of pressure and volume overload, such as uncontrolled hypertension, valve disorders such as aortic stenosis, this creates pressure and volume overload, and you get myocyte hypertrophy, which does result in left ventricular hypertrophy. Similarly, if you have a condition where you have a genetic mutation in the sarcomeric proteins, you can have hypertrophic cardiomyopathy, where you actually have pathologic hypertrophy of the myocytes and left ventricular hypertrophy. In these conditions, the voltage on the ECG is increased due to the myocyte hypertrophy. So as I mentioned, increased left ventricular wall thickening does not equate necessarily to left ventricular hypertrophy. So it is important to note that myocyte hypertrophy is not the only cause of an imaging evidence of an increase in left ventricular wall thickness. So more correctly, when you are looking at an echocardiogram and you measure that the walls are thicker than the normal limit, the knee jerk has to be that this is left ventricular wall thickening, not necessarily left ventricular hypertrophy. And the reason it's important to make that distinction is that there are infiltrative cardiomyopathies where there is deposition of material within the myocardium that is visualized on an imaging study such as an echocardiogram as increased wall thickness. It's important to note that the voltage on the ECG may not be increased, and sometimes, though not always, is decreased. And that has to do with the fact that the myocytes may not be significantly hypertrophied, but there is just thickening related to deposition. So the more accurate question is really, what is the differential diagnosis of increased left ventricular wall thickening? So I'd like to divide the differential diagnosis of left ventricular wall thickening into two buckets. One is conditions that cause myocyte hypertrophy. So I like to think of valve disease, aortic stenosis is probably the simplest example of aortic stenosis results in increased pressure volume overload of the left ventricle resulting in myocyte hypertrophy. Uncontrolled hypertension is another example of a condition that can cause myocyte hypertrophy. And then finally, hypertrophic cardiomyopathy is associated with myocyte hypertrophy. That is in contrast to other causes of increased left ventricular wall thickness, such as an infiltrative cardiomyopathy. So in a condition such as cardiac amyloidosis, in cardiac amyloidosis, you have misfolded amyloid proteins that are deposited within the myocardium, and the deposition of the amyloid protein results in left ventricular thickening. So that's an infiltrative cardiomyopathy. In addition, you can have inherited storage diseases where you have increased deposition of these storage materials that can cause the walls to thicken. So an example would be the lysosomal storage disease, Fabry's disease. So as I mentioned, the low voltage is something that can be seen in infiltrative cardiomyopathy, but it is not something that is needed. So in the case that I presented, that was kind of a misdirection, if you will, that the low voltage is not necessary to diagnose amyloidosis. What I think is perhaps more important is the discordance between the degree of left ventricular thickening on imaging versus what you see on an ECG. So in a condition such as aortic stenosis, you have increased voltage because you have myocyte hypertrophy. By contrast, in cardiac amyloidosis, there isn't true left ventricular hypertrophy. Rather, there is left ventricular thickening. And because there is not an associated myocyte hypertrophy, you do not see the increase in voltage. So if you see a wall thickness of 1.8 centimeters on an echo, but your ECG shows normal voltage, that should be a tip-off, perhaps, that there is an infiltrative condition. In addition on the ECG, you can find other changes in cardiac amyloidosis, some of which are very nonspecific. This includes a pseudo-infarction pattern of QS waves or poor R wave progression. You can have conduction delays, including AV block, nonspecific intraventricular conduction delays, a left bundle branch block, or a right bundle branch block. More extensive involvement in amyloid can result in atrial or ventricular arrhythmias. Another key piece is that a normal SPEP does not exclude cardiac amyloidosis. Unfortunately, that is a myth that is out there. A patient had a, quote unquote, normal SPEP, so can't have amyloid because the SPEP excludes amyloid. So it's important to step back and realize that among cardiac amyloidosis, there are really two main kinds of cardiac amyloidosis. The first involves the deposition of monoclonal immunoglobulin light chains that are produced by bone marrow plasma cell disorders. And this is what is called AL cardiac amyloidosis. And one of the diagnostic tests in the diagnostic algorithm for AL amyloidosis is an SPEP. Having said that, there is another kind of cardiac amyloidosis called amyloid transthyretin cardiomyopathy or ATTRCM, and this is a condition that has nothing to do with the light chain. An SPEP does not help you make the diagnosis of TTR except for the fact that it could be used as part of the diagnostic algorithm to exclude AL amyloidosis. So AL amyloidosis, yes, an SPEP is helpful. It's not alone sufficient, but there can still be patients with a normal SPEP that have a condition called ATTR cardiomyopathy. In ATTR cardiomyopathy, transthyretin, which is also called prealbumin, is a thyroxine and retinol binding protein that is produced by the liver, and this protein misfolds and is deposited in the heart, causing ATTR cardiomyopathy, and if it's deposited in the nerves, it can cause ATTR polyneuropathy. There are two varieties. There is what is called wild-type cardiac amyloidosis or ATTR WTCM, and in this condition, genetically normal TTR protein misfolds in aggregates with aging. This used to be called senile amyloidosis or aging-related ATTR cardiomyopathy. The more proper name for it now is wild-type cardiac amyloidosis. By contrast, there is another form of ATTR cardiomyopathy called variant cardiac amyloidosis. In this condition, abnormal TTR protein structure is the result of a mutation that renders the TTR protein prone to misfolding. So this used to be called familial ATTR cardiomyopathy or hereditary ATTR cardiomyopathy. Now it is called variant ATTR cardiomyopathy. So getting back to the normal SPEP, not excluding cardiac amyloid. So if you have someone that you are suspecting of having cardiac amyloidosis, it is critical that you perform a laboratory evaluation to exclude AL amyloidosis. And part of that exclusion of AL cardiac amyloidosis is ordering an SPEP. But the SPEP alone is actually not sensitive enough. So you need to order the SPEP or the serum protein electrophoresis with what is called an immunofixation electrophoresis or IFE. So in order to thoroughly rule out AL amyloidosis, you need to order an SPEP with immunofixation, a UPEP with immunofixation, and then perhaps most importantly, a serum-free light chains. Because all three of those, the SPEP with immunofixation, the UPEP with immunofixation, and the serum-free light chains are needed to exclude AL amyloidosis. Once you have excluded AL amyloidosis, you can use an imaging modality called the technetium pyrophosphate scan. And there are diagnostic algorithms that have been published that let you make a non-biopsy-based diagnosis of ATTR cardiomyopathy. So let's look at the cardiac clues or the cardiac red flags that should prompt an additional diagnostic evaluation for cardiac amyloidosis. So if you have a patient that has HFPEP with unexplained left ventricular hypertrophy, you should think about cardiac amyloidosis. And again, I will bring up the fact that it's not necessarily left ventricular hypertrophy, but if you have a patient with HFPEP and a wall thickness greater than 1.4 centimeters, that is something that you should really put on your diagnostic thinking cap and think, what is the differential? Is this simply uncontrolled hypertension? I think it is worth noting that patients that you see that have regular medical care that occasionally have a blood pressure of 140 over 90, but then they go home and they have some element of white coat elevated blood pressure and their blood pressure at home is in the 120s over 130s over 70s to 80s. Even if on occasion they come in and their blood pressure is 140 over 90 when you see them, that is not uncontrolled hypertension to a level where you would see a wall thickness of greater than 1.4 centimeters. If you had a patient with blood pressures of 190s to 200s over 100s, 110s for 20 years, that can cause significant left ventricular wall thickening and LVH, left ventricular hypertrophy. But in patients with reasonable blood pressure control, HFPEP and a wall thickness of greater than 1.4, amyloid is probably at the top of your differential. Another cardiac red flag is intolerance to antihypertensive medications or heart failure medications due to symptomatic hypotension or orthostasis. In the case example, a patient that is on metoprolol 25 milligrams twice a day and getting dizzy and lightheaded. If you have a patient that is on lisinopril two and a half milligrams a day and cannot tolerate anymore, that suggests that perhaps they have some level of autonomic dysfunction and autonomic involvement related to amyloid polyneuropathy and maybe that is why they cannot tolerate antihypertensive medications or heart failure medications. We talked about the discordance between LV wall thickness and what you see on the imaging test versus the ECG as a red flag. Persistent low level serum troponin elevation can be a red flag that amyloid may be present. Oftentimes patients with cardiac amyloidosis present to emergency rooms with chest pain or dyspnea and they have a troponin drawn and it is low level positive so patients end up getting ruled out for myocardial infarctions with persistently low level troponins. Sometimes that's attributed to demand ischemia. It's important to note that in patients with infiltrative conditions they can have a low level serum troponin elevation that can be persistently positive for quite some time. In patients with hypertrophic cardiomyopathy with certain additional findings such as pericardial infusion, EV block, intraatrial septal hypertrophy or the apical sparing pattern on strain imaging when patients get speckle tracking echo. That could be a suggestion that hypertrophic cardiomyopathy is not really the diagnosis but it's rather cardiac amyloidosis. It's also important to think about the demographics of the patient you're seeing. If you are seeing a 78 year old with new hypertrophic cardiomyopathy, in reality that patient more likely statistically has cardiac amyloidosis, particularly wild type ATTR cardiac amyloidosis as opposed to new hypertrophic cardiomyopathy in their late 70s. It's also important to think about unexplained wall thickening of the other chambers. We talk a lot about left ventricular wall thickening but if you have a patient with right ventricular wall thickening or atrial wall thickening and I think the intraatrial septum which is so clearly visualized on a simple imaging modality such as echocardiogram, that could be a tip-off that there's an infiltrative condition because the amyloid deposition and infiltration is not necessarily only in the left ventricle but can include all of the chambers of the heart. If you have a patient with unexplained AV block or prior pacemaker placement, that could be a suggestion that there is amyloidosis. And then finally a family history of cardiomyopathy, particularly if you expand beyond simply asking a patient whether they have a family history of amyloid. But if you ask about family history of cardiomyopathy, hypertensive heart disease, CHF, congestive heart failure, heart failure, enlarged heart, if you kind of broaden how you ask patients about the family history sometimes you will find that there is a pertinent family history present. Turning to the neurologic red flags, there are many patients that have concomitant amyloid affecting their nerves and they can have significant polyneuropathy that can manifest as paresthesias and weakness. This is particularly the case in variant ATTRCM. In addition, patients with autonomic dysfunction, orthostatic hypotension, and that contributes to the intolerance of standard antihypertensive medications and heart failure medications. Patients with postprandial diarrhea alternating with constipation sounds very similar to irritable bowel syndrome. That could be a manifestation of amyloid polyneuropathy. Gastroparesis and urinary retention in urinary incontinence could also be red flags that should suggest additional evaluation for cardiac amyloidosis. A family history of polyneuropathy is important to elicit in a similar fashion as the eliciting the family history of cardiomyopathy. And then finally, black race, the valine 122i mutation can be present in three to five percent of self-identified African Americans and it's important that in the right patient when there are red flags that amyloidosis should be on the differential and additional diagnostic evaluation should be performed. And finally, there are a number of orthopedic red flags that should prompt additional diagnostic evaluation for cardiac amyloidosis. Carpal tunnel syndrome is one of them and oftentimes patients have bilateral carpal tunnel syndrome. Sometimes this is blown off as occupational, people are on their computers, people are doing manual labor, but oftentimes amyloid patients will have bilateral carpal tunnel, even if they don't have an occupational history, and oftentimes they'll have recurrent symptoms. So even though they had a release 10 years ago, which should have been 100% successful, they are having recurrent symptoms and sometimes people are having multiple surgeries. That should be a big red flag that cardiac amyloidosis may be present. And additionally, lumbar spinal stenosis is a red flag, unprovoked bicep pain, is a red flag. Unprovoked biceps tendon rupture is a really interesting phenomenon. It's the Popeye muscle or Popeye deformity where unprovoked biceps tendon rupture should really make you think about cardiac amyloidosis. Sometimes patients come up with a reason. They will say they were carrying their toolbox or carrying groceries and that's what caused their muscle to pop. That is not usual. I would classify that as unprovoked. If somebody had a car accident, that's real trauma. That could be a cause, I suppose, of a biceps tendon rupture, but usual activities of daily living causing a biceps tendon rupture, you should really think about cardiac amyloidosis. The final orthopedic triggers include hip and knee replacement surgeries and trigger figure surgeries. The 2022 American Heart Association, American College of Cardiology, and Heart Failure Society guidelines did provide a diagnostic algorithm for diagnosis and treatment of trans-cyretin cardiac amyloidosis. When you have a patient with the historical right clinical scenario, including the clinical clues and red flags that we discussed, the first step is to order the labs to evaluate for a monoclonal light chain. If those monoclonal light chain labs come back abnormal, it is really important to talk to hematology oncology. A biopsy is usually what's going to be the next step, either a cardiac biopsy or a biopsy of the affected organ because a biopsy is required to make a diagnosis of AL cardiac amyloidosis. By contrast, if the monoclonal light chain labs come back normal, then the next step is to proceed with the technetium pyrophosphate scan. If the technetium pyrophosphate scan shows that there is evidence of TTR amyloidosis, then genetic testing can be used to separate ATTR variant from ATTR wild type, and then patients can subsequently receive the appropriate treatments for the condition. So this will be part of the ongoing lecture series in this topic. So in conclusion, it's important to recognize that an increased left ventricular wall thickness has a differential diagnosis. So you cannot assume that hypertension is the only cause of quote-unquote left ventricular hypertrophy. The second important point to note is that HEF-PEF plus unexplained left ventricular wall thickening of greater than 1.4 centimeters is rare in hypertension alone. So if you have HEF-PEF plus a wall thickness of greater than 1.4 centimeters, and there are those clinical clues or clinical red flags to suggest cardiac amyloidosis, additional diagnostic steps are required. The third concluding point is that cardiac amyloidosis is underdiagnosed. It is not rare, but simply un- or underdiagnosed. And if you do not think about amyloid, you will never make a diagnosis. So pay attention to those red flags. And the final and perhaps most important point to note is that cardiac amyloidosis is now treatable. This will be covered in other sessions, but because amyloidosis now has treatments, and because some of these treatments are actually associated with improved survival, it is critical to make a diagnosis because we do have treatment. This concludes the presentation. Thank you very much for your attention.

cardiac amyloidosis

unexplained ventricular thickening

ATTR cardiomyopathy

multiorgan symptoms

diagnostic evaluation

patient outcomes