Hi, my name is Amrath Ambedekar. I'm a professor of medicine at the University of Colorado, and I'm going to give you an overview about cardiac amyloidosis and specifically clinical clues for when you should think about doing testing to make a diagnosis of cardiac amyloidosis. If you look at amyloid at the system level, it turns out there are over 35 different amyloid precursor proteins throughout the human body. And the nomenclature for these proteins is the capital letter A for amyloid, followed by an abbreviation for that protein that misfolds. Thankfully in cardiology, there are really only one of two proteins that we need to focus on. The first is AL cardiac amyloidosis, where a monoclonal immunoglobulin light chain is produced by bone marrow plasma cells, and that's what's called AL cardiac amyloidosis. The second kind of amyloidosis that is the focus of this educational series is amyloid transthyretin cardiomyopathy, or ATTR cardiomyopathy, where the transthyretin protein, which is also known as prealbumin, is a thyroxine and retinol binding protein produced by the liver. There are two subtypes of ATTR cardiomyopathy. The first is wild-type cardiac amyloidosis, where there is genetically normal TTR protein that misfolds and aggregates with aging. This used to be called senile ATTR cardiomyopathy or aging-related ATTR cardiomyopathy, but the more proper term is wild-type cardiac amyloidosis. The second variety is what's called variant ATTR cardiomyopathy or mutant ATTR cardiomyopathy, where there is abnormal TTR protein structure that results from a mutation in the TTR gene that lends the protein to potentially misfold. Other names for this condition are familial ATTR cardiomyopathy or hereditary ATTR cardiomyopathy. So what does this cardiac amyloidosis look like? If you look at it microscopically, the top two images are what it looks like from a histology standpoint. So if you have aggregation of these insoluble fibrous deposits of beta sheets in the heart, you'll see what the first image looks like, which is the pink amorphous amyloid deposition seen. And what you see is that there's actual amyloid deposition and myocyte distortion and myocyte separation. If you look at this at an organ level, which is the second image on the bottom where you actually see an echocardiogram, you'll see that there is myocyte hypertrophy and thickening of the heart. You'll see diastolic dysfunction as well as restrictive cardiomyopathy and conduction abnormalities. It is a common myth that amyloid is a rare disease, and I think what I would like to dispel is that it is not a rare condition, but you have to think about amyloidosis. If it's not on your differential, you'll never make a diagnosis. So I will ask a rhetorical question, have you seen a patient with cardiac amyloidosis? And it turns out that you probably have. And after this educational session, hopefully you'll be able to recognize the clues and to lead yourself down the right diagnostic pathway. In a survey of patients with amyloid cardiomyopathy, the vast majority had seen five different physicians before making a diagnosis, over 50% of hereditary ATTR cardiomyopathy patients and almost 40% of wild-type ATTR cardiomyopathy patients were misdiagnosed with an alternate condition. 75% had received a treatment for that misdiagnosed condition, and hypertensive heart disease was the most common misdiagnosis. There are a number of patients out there that do not have a formal cardiac amyloidosis diagnosis. So while it is rare based on current epidemiology, there's actually a number of patients that do not have a formal diagnosis. And so if you look at patients that have HFPEF, anywhere from 12 to 20% of HFPEF patients may have a diagnosis of wild-type ATTR cardiomyopathy, particularly as you get into older populations. If you look at low-flow, low-gradient degenerative aortic stenosis patients, up to 12% may have wild-type ATTR cardiomyopathy. And so it's important to kind of think about what are the clues that should lead someone to think about making a diagnosis of amyloidosis. This table is a summary of the traditional cardiac clues, as well as non-cardiac clues that should prompt an astute clinician to think about a diagnosis of cardiac amyloidosis. The most important of which is if you have heart failure with preserved ejection fraction or HFPEF with unexplained left ventricular hypertrophy, or more accurately, left ventricular wall thickening. So if you see a wall thickness of greater than 1.4 centimeters, that is rare from uncontrolled hypertension alone. And so it's important to have a differential diagnosis for that increased wall thickening. And we'll cover that a little bit more. If you have hypertrophic cardiomyopathy with a pericardial effusion, AV block, intraatrial septal hypertrophy, or apical sparing, that should be a clue for cardiac amyloidosis. If there's a discordance between the left ventricular wall thickness that you see on an imaging and the voltage that you see on an electrocardiogram, that should be a clue to think about cardiac amyloidosis. It's important to note that a normal voltage on an ECG does not exclude a diagnosis of amyloidosis. And if you see left ventricular hypertrophy with symptoms of polyneuropathy or dysautonomia, or you see left ventricular hypertrophy with orthopedic manifestations, things like bilateral carpal tunnel syndrome, lumbar spinal stenosis, or spontaneous biceps tendon rupture, those should all be clues to think about going down the cardiac amyloidosis diagnostic pathways. So what is the differential diagnosis for left ventricular hypertrophy? And I have that in quotes, and we'll go over why. But left ventricular hypertrophy, or LVH, or left ventricular hypertrophy, is the result of myocyte hypertrophy. So if you have pressure-volume overload, such as in hypertension that's uncontrolled or aortic stenosis, or you have sarcomeric mutations that result in hypertrophic cardiomyopathy, you actually have myocyte hypertrophy that results in left ventricular hypertrophy. The voltage on the ECG is increased because of that myocyte hypertrophy. Increased left ventricular wall thickening is not the same as LVH though. So if you have myocyte hypertrophy, that is not the only cause of increased wall thickening. In conditions, infiltrative cardiomyopathy conditions can result in deposition of material within the myocardium that's visualized on imaging studies as an increase in wall thickening, but it does not associate with increased voltage on the ECG because there's not actual myocyte hypertrophy. So a more accurate question is, what is the differential diagnosis of increased left ventricular wall thickening? And it turns out that there's kind of two main causes of increased left ventricular wall thickening. One is conditions that cause myocyte hypertrophy, so that's conditions such as valve disease like aortic stenosis, uncontrolled hypertension, and hypertrophic cardiomyopathy, but the other causes include infiltrative cardiomyopathy, such as cardiac amyloidosis, as well as some more rare inherited storage diseases. And this is where that key distinction comes up, that you don't necessarily need a low voltage on the ECG to make a diagnosis of cardiac amyloidosis, but it's that discordance in the voltage that you see on the ECG versus the degree of left ventricular hypertrophy you see on the imaging test. And if you see that discordance, that should be a clue to think about cardiac amyloidosis. So we talked about echocardiography, what are the other echocardiographic clues that should raise suspicion for cardiac amyloidosis? So we spent a lot of time about left ventricular wall thickening, and that's certainly the most important clue. It turns out you can also see increased right ventricular wall thickening, and there's not a lot of conditions that give you the constellation of all of these echocardiographic findings. If you see increased right ventricular wall thickening, as well as increased left ventricular wall thickening, think about cardiac amyloidosis. You can see atrial enlargement, both left and right atrial enlargement. You can also sometimes see thickening of the atrial walls. On echo, the most easy place to see that is actually the intraatrial septum. You can see pericardial effusions in cardiac amyloidosis. There's a lot in echo books about the sparkling texture of the myocardium on echocardiography or the starry sky appearance, and that can certainly be a tip-off that an infiltrative condition is present. And then obviously all of the diastology parameters that we look at on echocardiography with abnormal tissue Doppler parameters and markers of left ventricular diastolic dysfunction can be a clue on echo that amyloidosis is present. If you look at more advanced echocardiography techniques, there are some clues that can be gained from speckle tracking echocardiography and specifically longitudinal strain. The longitudinal strain, which measures myocardial deformation, can help differentiate cardiac amyloidosis from other causes of increased wall thickening. And cardiac amyloidosis patients have a very characteristic pattern where they have decreased global longitudinal strain of their basal and mid-segments with preserved apical strain. So if you look at the top row of images, you'll see the strain values. The more negative values, the better the strain. So if you look at the apical segments, the strain is better, and if you look at the mid and the basal segments, the strain is worse. If you look at the bottom row of images, you'll see that there's a bullseye distribution map of the strain, and you'll see the characteristic cherry on top where you'll see preserved apical bearing strain versus decreased basal and mid-segment strain. And then finally, cardiac MRI is an additional imaging technique that can be helpful. So the top left image shows a four-chamber view on cardiac MRI of an amyloidosis patient. So we spent a lot of time talking about the wall thickening, and cardiac MRI is the gold standard, and you can see clear evidence of left ventricular wall thickening. You can also see increased right ventricular wall thickening, and you can also accurately measure the wall thickness of the atrial walls. In this image, you'll see that there's biatrial enlargement, and if you actually look at the intraatrial septum, there's clear evidence of thickening of the intraatrial septum in this amyloidosis patient. The middle image shows the parametric mapping, and cardiac amyloidosis patients have a characteristic phalaned native T1 as well as increased extracellular volume, which is characteristic of amyloidosis. And then finally, the picture on the right shows the late gadolinium enhancement imaging from this same patient. And cardiac amyloid patients have abnormal gadolinium kinetics, and they have abnormal late gadolinium enhancement, where you'll see diffused or sometimes transmural LGE in the left ventricle, right ventricle, and even sometimes the atrial walls, and you can see it in the intraatrial septum on this MRI image. So in summary, if you take all of the cardiac clues in total, the things that should really prompt an astute clinician to think about cardiac amyloidosis, most important is HEF-PEF with unexplained left ventricular wall thickening. A wall thickness of greater than 1.4 centimeters needs a differential diagnosis, and it is probably not just related to hypertension alone. If you have a patient that is intolerant to antihypertensive medications or heart failure medications due to symptomatic hypotension or orthostasis, that's a clue that amyloidosis may be present. We talked about the discordance between increased LV wall thickening on imaging versus not having that corresponding wall thickening, that voltage evidence of hypertrophy on the ECG. Patients with cardiac amyloidosis can have persistent low-level elevations and serum troponins. If you have what looks like hypertrophic cardiomyopathy on imaging with a pericardial effusion, AV block, intraatrial septal hypertrophy, or that apical sparing pattern on strain imaging, that is a clue for cardiac amyloidosis. When you have unexplained wall thickening of the right ventricular walls or atrial walls, that is a clue for amyloidosis. And then finally, unexplained AV block, prior pacemaker, or a family history of cardiomyopathy are all clues that amyloid may be present. In addition to the cardiac manifestations of cardiac amyloidosis, there are non-cardiac manifestations as well. Perhaps the most important of these are the neurologic manifestations. So if a patient has significant polyneuropathy, where they have paresthesias and weakness of their hands and feet, that should be a big red flag that amyloidosis may be present. Autonomic dysfunction and orthostatic hypotension can be present in cardiac amyloidosis patients. This is where the patients that cannot tolerate even the lowest doses of antihypertensive medications without having orthostasis, that's a red flag that amyloid might be present. There can be gastrointestinal manifestations from the autonomic dysfunction of cardiac amyloidosis patients can have alternating diarrhea and constipation, they can have gastroparesis, they can have urinary retention and incontinence. And then obviously a family history of polyneuropathy, a family history of amyloidosis should raise a big red flag that amyloid might be present. The valine isoleucine 122 mutation can be present in 3 to 5% of self-identified African-Americans. And so if the constellation of neurologic clues is there, additional diagnostic steps are needed to evaluate for cardiac amyloidosis. In addition, there are orthopedic manifestations that are often seen in patients with cardiac amyloidosis, carpal tunnel syndrome is common, oftentimes it is bilateral carpal tunnel syndrome, and often patients have had recurrent symptoms despite having prior release surgery. Patients with cardiac amyloidosis can have lumbar spinal stenosis, they can have unprovoked biceps tendon rupture, known as Popeye's muscle or Popeye deformity. And oftentimes this is unprovoked, or if it's provoked, it's in the setting of non-trauma or kind of usual activity. So a patient that's carrying a half a gallon of milk and has a spontaneous rupture of their biceps tendon, that is not normal or that's not provoked, and so that should raise suspicion for amyloidosis. Patients can have hip and knee replacements as well as multiple trigger finger surgeries or trigger finger injections from amyloidosis. So if you have a patient where there are clinical clues present that raise the suspicion of cardiac amyloidosis, it turns out there are a number of diagnostic pathways that are available. This is from the 2023 ACC ECDP statement, but there are similar ones from other professional societies that lead a clinician through a step-by-step way to make a diagnosis of cardiac amyloidosis. And oftentimes this can be made in a non-invasive way. So the first step is if you have clinical clues that you think amyloid is present, you start by screening for a monoclonal protein with simple labs, a serum and urine protein electrophoresis with immunofixation and a serum kappa to lambda light chain ratio. If these labs come back abnormal, it will require additional investigation, oftentimes consultation with a hematologist, and potential biopsy. However, if the screening labs for a monoclonal protein come back normal, the next step is to do a technetium pyrophosphate scan, which is a non-invasive imaging test available in most nuclear cardiology labs. And if this technetium pyrophosphate scan comes back normal, cardiac amyloidosis is unlikely. But if it comes back suggestive of cardiac amyloidosis, then with genetic testing you can make a diagnosis of either variant ATTR cardiomyopathy or wild-type ATTR cardiomyopathy. So in conclusion, increased left ventricular wall thickness has a differential diagnosis. Don't assume that hypertension is the only cause of LBH. HEF-PEF plus unexplained left ventricular wall thickening of greater than 1.4 centimeters is rare in hypertension alone. And if there are additional clinical clues to suggest amyloidosis is present, additional diagnostic steps are required. Cardiac amyloidosis is underdiagnosed, but it is not rare. But if you don't think about it, you'll never make a diagnosis. And now there are a number of published diagnostic pathways that allow for a non-invasive diagnosis of cardiac amyloidosis in many cases. And perhaps what's most exciting is that cardiac amyloidosis is now treatable. So it's not that you're just making a diagnosis for the sake of making a diagnosis. There are now life-saving treatments available, and if started early, can have significant improvement in patient outcomes. Thank you very much.

cardiac amyloidosis

AL amyloidosis

ATTR amyloidosis

echocardiographic findings

early diagnosis